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Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB–mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell–to–T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell–Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.

Background: Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long lasting eradication of the disease only in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in BM a/o PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts with MRD+ by both NEST and RQ in BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results: Of the 106 evaluable pts, 50 were males. Median age was 55 y (29-83). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68% of pts had inguinal site involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/ o PB;the concordance between compartments was 90%. All but one pt achieved a clinical response after IFRT;one additional pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2/IGH+ cells in PB a/o BM in 60% of pts. MRD + pts, either after IFRT (n = 18) or in case of conversion to MRD+ during the follow-up (n = 6), received OFA, obtaining a conversion to MRD-in 22/24 pts (91.7%-CI 73.0-99.0), significantly superior to the expected 50% (Fig). After a median F-U of 38 m, 17 pts who achieved a MRD-with OFA are still negative;5 converted to MRD+ (2 received OFA retreatment, achieving a second MRD-;2 pts were not re-treated due to Sars-Cov2 pandemic;1 relapsed). A clinical relapse or progression was observed in 23 pts: 18 (24.6%) among the 73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+ at baseline (p = 0.3), with no significant difference in PFS (p = 0.25). Two early relapses were observed among the 12 pts who became MRD-after IFRT and 3 among the 24 treated at least once with OFA (1 MRD+, 1 MRD-, 1 converted from MRD-to MRD+). Only 1 Pt relapsed while MRD-after OFA. Conclusions: MRD data indicate that RT alone is often insufficient to eradicate the disease, inducing a MRD-only in 40% of pts, notably long-lasting only in half of them. The primary objective of this study-MRD conversion after immunotherapy-was largely achieved. The strategy of an immunotherapy consolidation after IFRT in MRD+ pts allowed increasing molecular responses. However, this strategy is applicable only to 30% of enrolled pts. A clinical advantage of the MRD driven treatment strategy is suggested although not significan.

Background: Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients. Methods: One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19. Results: Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P =.02) and uninfected hematologic controls (3%; P

The complete remission (CR) rate achieved with induction chemotherapy prior to autologous stem cell transplantation (ASCT) represents the strongest prognostic factor in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). By inducing a CR rate of 75%, the bendamustine, gemcitabine, vinorelbine (BEGEV) regimen represents an optimal chemotherapy regimen prior to ASCT. Presented here are the 5-year results of BEGEV followed by ASCT in R/R cHL. With a median follow-up of 5 years, progression-free survival (PFS) and overall survival (OS) for the whole series (n = 59) were 59% and 78%, respectively. ASCT was performed in 43 of 49 responding patients (73% by intention to treat [ITT]; 88% by response to BEGEV) and resulted in 33 with continuous CR (56% by ITT; 77% of transplanted patients), 7 with disease relapse, and 3 with nonrelapse mortality. For patients who received transplants, the 5-year PFS and OS were 77% and 91%, respectively, with no significant difference between relapsed and refractory patients. No patient experienced secondary leukemia or myelodysplasia. In summary, the long-term efficacy data, the benefits for both relapsed and refractory patients, and the excellent safety profile provide a strong rationale for further development of the BEGEV regimen. This trial was registered at EudraCT as #2010-022169-91 and at www.clinicaltrials.gov as #NCT01884441.

// Antonio Sacco 1 , Adriano Fenotti 2 , Loredana Affo 2 , Stefano Bazzana 3 , Domenico Russo 4 , Marco Presta 5 , Michele Malagola 4 , Antonella Anastasia 6 , Marina Motta 6 , Christopher J. Patterson 7 , Giuseppe Rossi 6 , Luisa Imberti 1 , Steven P. Treon 7 , Irene M. Ghobrial 7 and Aldo M. Roccaro 1 1 ASST Spedali Civili, Coordinamento e Progettazione Ricerca Clinica, CREA Laboratory, Brescia, BS, Italy 2 ASST Spedali Civili, SITRA, Brescia, BS, Italy 3 ASST Spedali Civili, Collegio IPASVI, Brescia, BS, Italy 4 University of Brescia Medical School, Adult Bone Marrow Transplantation Unit, Brescia, BS, Italy 5 University of Brescia Medical School, Dept. of Molecular and Translational Medicine, Brescia, BS, Italy 6 ASST Spedali Civili, Dept. of Hematology, Brescia, BS, Italy 7 Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Boston, MA, USA Correspondence to: Aldo M. Roccaro, email: // Keywords : Waldenstrom’s Macrolobulinemia, genomics Received : November 17, 2016 Accepted : February 20, 2017 Published : March 11, 2017 Abstract The Literature has recently reported on the importance of genomics in the field of hematologic malignancies, including B-cell lymphoproliferative disorders such as Waldenstrom’s Macrolgobulinemia (WM). Particularly, whole exome sequencing has led to the identification of the MYD88 L265P and CXCR4 C1013G somatic variants in WM, occurring in about 90% and 30% of the patients, respectively. Subsequently, functional studies have demonstrated their functional role in supporting WM pathogenesis and disease progression, both in vitro and in vivo , thus providing the pre-clinical evidences for extremely attractive targets for novel therapeutic interventions in WM. Of note, recent evidences have also approached and defined the transcriptome profiling of WM cells, revealing a signature that mirrors the somatic aberrations demonstrated within the tumor clone. A parallel research field has also reported on microRNAs (miRNAs), highlighting the oncogenic role of miRNA-155 in WM. In the present review, we focus on the latest reports on genomics and miRNAs in WM, providing an overview of the clinical relevance of the latest acquired knowledge about genomics and miRNA aberrations in WM.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment. We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p= 2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80% Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tedeschi:Abbvie: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Falini:Roche: Research Funding. Pulsoni:Sandoz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; roche: Consultancy, Speakers Bureau; Merk: Consultancy. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Zinzani:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenstrom's Macroglobulinemia (WM). Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We investigated the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule, NSC12, a small molecule identified using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2. By interrogating the transcriptome signature of patients' BM-derived CD19-positive cells (GEO9656, GEO6691), we found a significant enrichment of FGF/FGFR-driven signaling cascades, including PI3K-AKT, MAPK and STAT3 pathways (FDR In addition, the NSC12-dependent inhibition of MYD88 resulted in silencing of the MAPK-ERK signaling cascade, thus leading to NSC12-induced Myc-silencing in WM cells. We next confirmed the efficacy of NSC12 in silencing bone marrow stromal cell (BMSC)-induced FGFR3 phosphorylation; paralleled by inhibition of of pro-survival pathways, including pAKT, the AKT-downstream pGSK3β; p-ERK; and p-STAT3. Functional sequelae of the FGF/FGFR blockade in WM cells were studied, demonstrating inhibition of WM cell growth, induction of apoptosis, enhanced ER stress and initiation of UPR. Of note, anti-WM activity of NSC12 was also documented using primary bone marrow-derived CD19+ cells isolated from patients with WM. In contrast, NSC12 did not show cytotoxicity on PBMC-derived CD19+ cells isolated from healthy donors. The anti-WM activity exerted by NSC12 was confirmed also within the context of the supportive bone marrow milieu, as shown both in vitro and in vivo. BCWM.1, MWCL1 cells were cultured with NSC12 in the presence or absence of primary WM BMSCs: adherence of WM cells to BMSCs triggered a significant increase in the proliferation, which was inhibited by NSC12in a dose-dependent manner (P Overall, our studies are reporting on the use of NSC12, as a novel potential therapeutic strategy to specifically halt the FGF/FGFR axis in WM; and demonstrate how the observed anti-WM activity exerted by NSC12 may be driven, at least in part, by inhibition of MYD88. Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Rossi:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roccaro:Amgen: Other; AstraZeneca: Research Funding; Celgene: Other; Janssen: Other; Italian Association for Cancer Research (AIRC): Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding.

Purpose The clinical impact of positron emission tomography (PET) evaluation performed early during first-line therapy in patients with advanced-stage Hodgkin lymphoma, in terms of providing a rationale to shift patients who respond poorly onto a more intensive regimen (PET response-adapted therapy), remains to be confirmed. Patients and Methods The phase II part of the multicenter HD0801 study involved 519 patients with advanced-stage de novo Hodgkin lymphoma who received an initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and who underwent an early ifosfamide-containing salvage treatment followed by stem-cell transplantation if they showed a positive PET evaluation after two cycles of chemotherapy (PET2). The primary end point was 2-year progression-free survival calculated for both PET2-negative patients (who completed a full six cycles of ABVD treatment) and PET2-positive patients. Overall survival was a secondary end point. Results In all, 103 of the 512 evaluable patients were PET2 positive. Among them, 81 received the scheduled salvage regimen with transplantation, 15 remained on ABVD (physician’s decision, mostly because of minimally positive PET2), five received an alternative treatment, and two were excluded because of diagnostic error. On intention-to-treat analysis, the 2-year progression-free survival was 76% for PET2-positive patients (regardless of the salvage treatment they received) and 81% for PET2-negative patients. Conclusion Patients with advanced-stage Hodgkin lymphoma for whom treatment was at high risk of failing appear to benefit from early treatment intensification with autologous transplantation, as indicated by the possibility of successful salvage treatment in more than 70% of PET2-positive patients through obtaining the same 2-year progression-free survival as the PET2-negative subgroup.

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

Aim Assessment of hematologic improvement, survival and peri-operative morbidity after first-line splenectomy for splenic marginal zone lymphoma (SMZL). Methods Forty-three patients undergoing open splenectomy were prospectively analyzed. Perioperative clinical course, overall and progression-free survival (OS-PFS) were evaluated. Risk factors analyzed were gender, age, ASA-grade, ECOG performance status, presence of B-symptoms, body mass index, steroidal treatment, serum albumin concentration, IIL-score, operative time, spleen size and weight. Results The median follow-up was 31 months (IQR 15–76; range 24–154). Anemia and thrombocytopenia resolved in 80% of patients at 6 months; in 60% at 2 years. The 5-year and 10-year PFS were 35% and 13% respectively, with a median of 35 months (shorter in patients with ECOG performance status ≥2 and B-symptoms). Nineteen cases (44.2%) had a progression of disease within 2 years. Of these, 14 (32.6%) received adjuvant chemotherapy (mainly R-FC or R-CVP). Progression was attributed to high-grade B lymphoma in 7 (16.3%) patients. The median time between diagnosis and progression to aggressive lymphoma was 25.5 months (range 18.8–81.8). The median time to next treatment was 83.5 months (95% CI 49–118). The 5-year and 10-year OS were 75% and 53% respectively. Mortality was due to disease progression and histological transformation in high-grade B lymphoma in 50% of cases, myelodisplastic syndrome in 15%, recurrence of hemolytic anemia in 15%, Hodgkin lymphoma in 7% and to infections (mainly pulmonary) in the remaining 13% of cases. Post-operative morbidity was 2.3% (1 patient with grade-3 complication). Overall grade ≥2 complication rate was 32.5% (mainly hemorrhagic and pulmonary complications). Spleen weight was the only independent risk factor for morbidity. Mortality was nil. Conclusion Splenectomy is safe and effective as regards cytopenia resolution and OS, although disease progression is frequently observed at follow-up. Such results are strictly linked to accurate pre- and post-operative clinical management and optimal anesthesiologic approach.

The human fibroblast growth factor receptor (FGF-R) family plays an essential role in a wide range of cellular processes, such as cell growth, proliferation, differentiation, migration and survival. It has been reported that FGF-Rs are expressed in hematopoietic cells; and FGF/FGFR signaling deregulation is largely involved in hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb due to disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGF-R system in FGF-dependent WM cell lines by using an anti-pan FGF trap molecule (NSC12), responsible for FGF/FGF-R blocking. We first interrogated the GSE9656 dataset in order to confirm the expression of FGFs and FGF-Rs in WM cells, demonstrating an enrichment of several FGF- and FGF-R-isoforms in primary WM patients' derived tumor cells compared to the normal cellular counterpart (P Disclosures Ronca: Associazione Italiana per la Ricerca sul Canctro (AIRC): Research Funding. Rossi:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Roccaro:AstraZeneca: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; European Hematology Association: Research Funding; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; Transcan2-ERANET: Research Funding; AstraZeneca: Research Funding; European Hematology Association: Research Funding; Transcan2-ERANET: Research Funding.

Introduction Limited stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), although different approaches are currently carried out, ranging from watch and wait to combined treatment. RT on involved lymph nodes allows eradication of the disease only in 40-50% of patients. Anti-CD20 monoclonal antibodies (MoAb), widely used in advanced stage FL, are likely to be effective in reducing the relapse risk, although no scientific evidence of their role has been provided. The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying patients unlikely to be cured by RT, for whom an immunotherapy-based consolidation could improve outcome. Methods 110 patients with stage I/II FL were enrolled. IFRT was administered to all patients at a dose of 24 Gy. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the Italian FIL (Federazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories: the presence of a BCL2/IGH rearrangement was investigated at baseline in all patients by nested PCR (NEST) and RQ-PCR (RQ), the latter according to the EuroMRD guidelines. In patients BCL2/IGH+ at baseline by both NEST and RQ in BM and/or PB, MRD was analyzed in both tissues after IFRT and every 6 months over a three-year follow-up period. Patients with positive MRD by both NEST and RQ in BM and/or PB after IFRT or who became positive during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab. The primary objective of the study was to define the efficacy of immunotherapy in obtaining the disappearance of BCL2/IGH rearranged cells. Results Preliminary data are available for 107 patients, 57 males, 50 females. Median age was 55 years (29-83). 17% had G1 FL, 32% G2, 40% G3A, 11% NOS. The FLIPI score was 0 in 59% of patients, 1 in 35%, 2 in 6%. 69% of patients had inguinal site involvement. Despite a negative BM biopsy, at baseline 30% of patients (n=32) had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in the BM and/or PB; the concordance between compartments was 90%, with 10% of negative PB showing a positive BM. No significant differences were observed in relapse probability between patients with or without a molecular marker. All patients were submitted to IFRT and all obtained a clinical response, which was complete in 79 of the 101 evaluated patients (78%) and partial in 22 (22%). MRD evaluation after treatment revealed the persistence of BCL2/IGH rearranged cells in the PB and/or BM in 60% of patients. According to the design of the protocol, MRD-positive patients, either after IFRT (n=18) or in case of conversion to a positive signal during the follow-up (n=7), received 8 weekly administration of ofatumumab. A conversion to MRD negativity, evaluated in 23 treated patients, was obtained in 20 (87% - CI 65.1-97.1). This result was significantly superior to the expected 50%. One death occurred after IFRT, due to ischemic stroke. Adverse events likely correlated to ofatumumab occurred in 7/25 treated patients, consisting of infusion reactions in 5, leading to a permanent interruption of immunotherapy in 3. After a median follow-up of 18 months, all patients who achieved a MRD negativity with ofatumumab underwent a regular molecular follow-up and are still MRD-negative. Overall, clinical relapse or progression were observed in 17 patients: 13 (18%) among the 73 "no marker" patients; 2 relapses (16%) were observed among the 12 MRD-negative patients after IFRT and 2 relapses were observed among the 23 patients treated with the anti-CD20 MoAb (8.7%), 1 having achieved a MRD negativity and 1 not. No significant differences in event-free survival have so far been observed between the three groups. Conclusions The MRD data of this phase II trial for early stage FL indicate that RT alone is often insufficient to eradicate the disease, being capable of inducing a negative MRD only in 40% of evaluable cases, with a long-lasting effect only in half of them. The primary objective of this study - MRD negativity after immunotherapy - was achieved, obtaining the disappearance of BCL2/IGH rearranged cells in the majority of patients treated with ofatumumab. The strategy of an immunotherapy consolidation after IFRT in MRD-positive patients allowed to increase molecular responses. A longer follow-up and further studies on larger patient populations will allow to conclusively define the impact of this MRD-driven strategy also on clinical outcome. Disclosures Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Gilead: Speakers Bureau; Merk: Consultancy; Bristol Meyer Squibb: Speakers Bureau. Ferrero:Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer . Liberati:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Janssen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Novartis: Other: Clinical trial support. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Corradini:Roche: Honoraria; Novartis: Honoraria; kite: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Mannina:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcaini:Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ladetto:AbbVie: Honoraria; Roche: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; J&J: Honoraria; Celgene: Honoraria. Foà:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: The anti-CD20 MoAb Ofatumomab is employed to eradicate Minimal Residual Disease in early stage Follicular Lymphoma(FL). The drug is registered for Chronic Lymphocytic Leukemia, not for FL.

This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m(2)) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%; p = 0.002) and OS (two-year OS: 100% vs 76%; p

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma in western countries. Overall, 70% of patients achieve complete remission after first treatment.[1][1] However, it is characterized by a pattern of relapsing and remitting disease. The outcome of patients with FL has clearly

Purpose This multicenter, open-label, phase II study evaluated the combination of bendamustine, gemcitabine, and vinorelbine (BeGEV) as induction therapy before autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (HL). Patients and Methods Patients with HL who were refractory to or had relapsed after one previous chemotherapy line were eligible. The primary end point was complete response (CR) rate after four cycles of therapy. Secondary end points were: overall response rate, stem-cell mobilization activity, and toxicity. Progression-free and overall survival were also evaluated. Results In total, 59 patients were enrolled. After four cycles of therapy, 43 patients (73%) achieved CR, and six (10%) achieved partial response, for an overall response rate of 83%. The most common grade 3 to 4 nonhematologic toxicities included febrile neutropenia (n = 7) and infection (n = 4). Regarding hematologic toxicities, grade 3 to 4 thrombocytopenia and neutropenia were each experienced by eight patients (13.5%). CD34+ cells were successfully harvested in 55 of 57 evaluable patients, and 43 of 49 responding patients underwent ASCT. With a median follow-up of 29 months, the 2-year progression-free and overall survival rates for the total population were 62.2% and 77.6%, respectively. The same figures for patients undergoing autograft were 80.8% and 89.3%, respectively. Conclusion This phase II study demonstrates that BeGEV is an effective salvage regimen able to induce CR in a high proportion of patients with relapsed or refractory HL before ASCT. These data provide a strong rationale for further development of the BeGEV regimen.

Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P

There is a significant need to develop an efficient treatment, without sacrificing efficacy, for older fit patients with chronic lymphocytic leukemia (CLL) as fludarabine, cyclophosphamide and rituximab (FCR) have very often led to treatment-related toxicities, causing delay or therapy

Introduction: Advanced stage follicular lymphoma (FL) is generally considered incurable. Although multiple remissions after treatment are possible, relapse is considered the rule, and the time to progression tends to become shorter after each relapse (Johnson, JCO 1995). Over the last decades, after the introduction of monoclonal anti-CD20 antibodies and of better treatment programs, the prognosis of FL has markedly improved from a median OS of 7 years to a 10-year OS rate >80%. Moreover, clinical observations of patients (pts) experiencing very long progression-free periods despite more than one previous treatment failure, have become not rare, suggesting that some pts could achieve operational FL cure. To assess the frequency of those prolonged long-term remissions and search for potential predictive factors, we have retrospectively analyzed the consecutive series of pts with FL seen at our institution. Methods: FL pts, aged >18 years, in maintained remission for more than 5 years after at least two lines of treatment were selected as "potentially cured" FL (PC-FL) and analyzed in detail. Their main characteristics at diagnosis and at last relapse, the different lines of treatment received and the time intervals (time to next treatment: TTNT) between them, were recorded and compared with those of FL pts seen in the same period (control group). Treatment strategies used were grouped and defined as follows: radiotherapy or surgery, for stage I-II (local), anthracycline and/or alkylating agents regimens (Alk/Ant), purine analogues regimens (Pur), monoclonal antibodies/radioimmunoconjugates as single agent (MoAb), autologous transplantation (ASCT). Results and discussion: Among 385 consecutive FL pts seen from January 1987 to December 2011, 56 (14,5%) met criteria for PC-FL. Their clinicopathological features at diagnosis, compared to controls, are shown in Table I. There were no significant differences except for a younger age (51 vs 58 years, p Conclusions: Approximately 15% of FL pts could currently achieve a very prolonged remission of about 10 years, even after multiple relapses. Its duration was 5x that of the last treatment line and more than twice that of active lymphoma, strongly suggesting the possibility of having achieved lymphoma cure. Younger age and grade 1-2 FL histology at diagnosis, and FLIPI low risk at relapse favored the achievement of PC-FL status. No specific treatment was associated with PC-FL and even an early relapse after first line treatment did not preclude to reach PC-FL, although early ASCT may be more effective for POD24 patients. Whether the achievement of PC-FL status may be related to biological factors will be interesting to be investigated in the next future. Disclosures Rossi: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria.

INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (Auto-SCT) in chemosensitive patients still remains the standard-of-care treatment for relapsed/refractory classic Hodgkin lymphoma (R/R CHL). As previously reported in a multicenter phase 2 study (Santoro et al., J Clin Oncol, 2016), the BEGEVregimen induces an objective response rate (ORR) >80% in the second-line salvage setting of R/R cHL, thereby resulting a highly effective treatment. Here, we assess efficacy and safety of the BEGEV regimen after extended follow-up (registered at www.clinicaltrials.gov as #NCT01884441). PATIENTS AND METHODS: cHL patients who were refractory to, or have relapsed after first-line chemotherapy were eligible. The primary endpoint was CR rate after 4 cycles of therapy. Secondary endpoints were: ORR, stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. The BEGEV regimen consisted of: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every 3 weeks for a total of 4 courses. RESULTS: Between September 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) cHL were enrolled. The median age was 33 years (range 18-68). By intention to treat (ITT), after 4 cycles of therapy, 44 (75%) achieved a CR and 5 (8%) a partial response (PR) for an ORR of 83%. One case (2%) showed stable disease (SD), while 8 patients (14%) progressed, and 1 (2%) was not evaluable for response. In univariate analysis, the only factor which resulted associated with a different probability to reach CR was disease status at study entry, with CR being achieved by 84% of relapsed patients and 59% of refractory patients (P=0.031). With a median follow-up of 56 months (range, 3.4-79), the overall patient population (n=59) has an OS of 78% and a PFS of 61%, respectively, without significant difference between relapsed and refractory patients. Fifty-seven out of 59 patients were evaluable for CD34+ cell mobilization. Two of 57 patients (3.5%) experienced CD34+ cell mobilization failure, whereas the planned target dose of CD34+ cells (3×10^6 CD34+ cells/Kg body weight) was successfully harvested in the remaining 55 patients (96.5%). After AutoSCT, engraftment of neutrophils and platelets was recorded on day 11 (range 9-21) and day 12 (range 9 - 26), respectively. Of the 49 responding patients, 43 (73% by intention to treat) proceeded to Auto-SCT (39/43 in CR, 4/5 in PR); the remaining 6 patients did not proceed to Auto-SCT due to mobilization failure (n=2), physician decision (n=2), early relapse (n=1), patient refusal (n=1).After transplant, 4 patients died [pneumonia (n=1), infection (n=1), multi-organ failure (n=1), PD (n=1)] and 7 patients relapsed. No patient has developed secondary leukemia or myelodysplasia. For transplanted patients, the 5-yr OS and PFS are 91% and 77%, respectively. CONCLUSIONS: These 5-year follow-up data demonstrate that BEGEV is a highly effective and safe salvage regimen. Nearly 80% of BEGEV-treated R/R cHL patients who experience an objective response and are addressed to Auto-SCT achieve long-term disease control and may potentially be cured. These data provide a strong rationale for further development of the BEGEV regimen. Disclosures Luminari: Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Servier: Consultancy; Sandoz: Consultancy. Carlo-Stella:ADC Therapeutics: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; AstraZeneca: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Genenta Science: Speakers Bureau; MSD Italia: Speakers Bureau.

This retrospective study evaluated whether early 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) after two cycles of salvage chemotherapy (PET2) could predict survival after high-dose chemotherapy (HDC). Twenty-four Hodgkin lymphoma (HL) patients were included. PET2 was negative in 58% and positive in 42% of patients. Ninety per cent of patients (9/10) with positive PET2 relapsed after HDC while all but one patient with negative PET2 maintained a complete remission. The 2-year progression-free survival was 93% vs. 10% for patients with negative and positive PET2, respectively (P < 0.001). This study shows that interim PET can predict the outcome after high-dose chemotherapy in HL patients.

Background: We analysed the feasibility and efficacy of allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning (RIC) in patients with refractory or progressive Hodgkin's disease (HD) after high-dose chemotherapy (HDCT). Patients and methods: Fourteen patients with HD received allo-SCT with RIC: eleven patients had a human leucocytes antigen-identical related donor and three a matched unrelated donor. Six had chemoresistant disease and eight had chemosensitive one at the time of transplantation. All patients received a fludarabine-based RIC. Results: All patients engrafted and full donor chimerism was achieved in all patients. Grade II acute graft-vs.-host disease (GvHD) developed in six of the 14 patients (43%). Chronic GvHD developed in eight of the 13 patients (61%). There was neither early nor late treatment-related mortality (TRM). With a median follow-up of 21 months (range 3-74), 10 of the 14 patients were alive (71%). Estimated overall survival at 1 and 2 yr was 93% and 73%, respectively, for the whole population, 83% and 44% respectively for patients with chemoresistant disease and 100% for those with chemosensitive disease. Estimated progression-free survival at 1 yr was 36%; 62.5% for chemosensitive patients and 0% for those with chemoresistant disease. Conclusions: In conclusion, allo-SCT with fludarabine-based RIC is a feasible procedure, without TRM in HD patients relapsed and refractory after HDCT. Even if several questions are still open, this approach should proposed for these poor prognosis patients.

BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

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

Clinical trial results indicate that brentuximab vedotin brings considerable promise for the treatment of patients with relapsed or refractory Hodgkin’s lymphoma. A retrospective multicenter study was conducted on 65 heavily pretreated patients who underwent therapy through a Named Patient Program in Italy (non trial-setting). The primary study endpoint was the objective response rate; secondary endpoints were safety, overall survival and progression-free survival. The best overall response rate (70.7%), including 21.5% complete responses, was observed at the first restaging after the third cycle of treatment. After a median follow up of 13.2 months, the overall survival rate at 20 months was 73.8% while the progression-free survival rate at 20 months was 24.2%. Globally nine patients are in continuous complete response with a median follow up of 14 months (range, 10–19 months). Four patients proceeded to autotransplantation and nine to allotransplantation. The most frequent extra-hematologic toxicity was peripheral neuropathy, observed in 21.5% of cases (9 patients with grade 1/2 and 5 patients with grade 3/4); neurological toxicity led to discontinuation of treatment in three patients and to dose reduction in four. In general the treatment was well tolerated and toxicities, both hematologic and extra-hematologic, were manageable. This report indicates and confirms that brentuximab vedotin as a single agent is effective and safe also when used in standard, everyday clinical practice outside a clinical trial. Best overall responses were recorded after three or four cycles and showed that brentuximab vedotin provides an effective bridge to further therapeutic interventions.

Introduction Phosphoinositide-3-kinases (PI3Ks) are pivotal in various cellular functions including proliferation and survival, cell differentiation, intracellular trafficking and immunity. The PI3Kδ isoform is highly expressed in cells of hematopoietic origin, and is often dysregulated in various hematologic malignancies. New drugs targeting PI3Ks have emerged as promising treatment options for patients (pts) with CLL and indolent NHL, but a clear understanding of their effects on pts' immunity is lacking. Herein we performed detailed immunological analysis in two follicular lymphoma (FL) pts treated with PI3K inhibitors and developing severe immune-mediated side effects. Patients and Methods Two of 9 pts with relapsed FL treated with PI3Kδ (pt1) and PI3Kα/δ (pt2) inhibitors developed severe adverse events (SAE). Both pts were heavily pretreated including autologous transplantation and discontinued therapy due to SAE. Pt1 showed grade 3 transaminase elevation, esophagitis and diarrhea requiring hospitalization after 3 cycles of therapy. Diarrhea worsened with fever and weight loss, in spite of transient discontinuation and dose reduction of PI3k inhibitor. Colonoscopic biopsy showed GVHD-like colitis. He died 3 months later. Pt2 has developed, after the first cycle and over a period of one year, febrile neutropenia, erythroderma, ulcerative keratitis requiring corneal transplant, pure red cell aplasia, endocrine abnormalities, grade 3 diarrhea with weight loss, and inflammatory bowel disease-like colitis. Detailed T-cell subpopulations immunophenotyping and T-cell receptor (TCR) spectratyping were performed in samples obtained at 6 months and 1 year after the start of treatment. Results Compared to healthy controls (HC) both pts showed marked abnormalities in T-cell subsets including a very low percentage of CD4+CD45RA+CCR7+CD31+ recent T-emigrants (RTE) and of CD4+CD45RA+CCR7+ naïve T cells in both CD4+ and CD8+ populations; CD4+CD45RA-CCR7+ central memory were significantly decreased, while CD4+CD45RA-CCR7- effector memory T cells were increased. Natural CD4+CD25+CD127low/- regulatory T cell (Treg) were low in both pts and the defect equally involved naïve, central and effector memory Treg. On the contrary, inducible Treg (Tr1) did not differ between FL pts and HC. The predominance of effector T cells strongly biased the TCR repertoire. Cells expressing all TCR beta variable (BV) chains were clonally or oligoclonally expanded at the spectratyping analysis because their profiles deviated from the Gaussian patterns found in polyclonal repertoires of HC. Discussion The clinical picture of the two FL pts was reminiscent of congenital immunodeficiencies with defects of Treg activity (e.g. IPEX caused by FoxP3 gene mutation). Similar symptoms and T-cell abnormalities are also present in pts with inadequate thymic function and immunologic reconstitution due to severe chronic GVHD. The associated T-cell immunological derangement was characterized by: 1) a marked reduction of the thymic output; 2) a clear defect in natural Treg; 3) an increase of peripheral oligoclonal effector memory T cells. Preclinical data on the role of PI3kδ support its possible pathogenetic involvement: PI3Kδ is known to play critical roles during thymopoiesis and its deletion/inactivation results in a block at the CD4 CD8 double negative stage of T-cell development. In mice with a mutation of PI3Kδ subunit, Treg were increased in the thymus but decreased in all peripheral immune organs, suggesting an impaired emigration of these cells from the thymus. Moreover, mice expressing an inactive form of PI3Kδ develop inflammatory bowel disease. These preliminary data suggest that small molecule-mediated inhibition of PI3Kδ may cause severe alterations within the T-cell compartment in selected pts, which may derive from a defect in the thymic output, including that of Treg. The generation of mature, oligoclonal T cells can be either the result of an homeostatic T-cell proliferation or of a strong (auto)antigenic stimulation. To better elucidate such mechanisms, further studies are in progress on a larger number of pts showing different levels of PI3k inhibitor toxicity. Nevertheless, we suggest that a close follow-up of lymphocyte subpopulation changes should be worthwhile since it may anticipate the onset of these severe clinical manifestations. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for refractory/relapsed (R/R) Hodgkin lymphoma (HL). Achieving complete remission (CR) prior to ASCT represents the strongest prognostic factor for R/R HL patients receiving salvage chemotherapy. Therefore, increasing the CR rate prior to ASCT represents a primary goal in these patients. Since Bendamustine monotherapy induces CR in a substantial proportion (25% to 35%) of R/R HL patients, the present phase II study aimed at investigating efficacy and toxicity of a novel salvage regimen combining Bendamustine, Gemcitabine and Vinorelbine (BeGEV) as second-line salvage chemotherapy in patients with relapsed/refractory HL. PATIENTS AND METHODS: HL patients who were refractory to, or have relapsed after one previous chemotherapy line were eligible. The primary endpoint was CR rate after four cycles of therapy. Secondary endpoints were: overall response rate (ORR), stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. BeGEV regimen consisted of: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every 3 weeks for a total of 4 courses. RESULTS: Between August 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) HL were enrolled. The median age was 33 years (range 18-68). Out of 59 enrolled patients, 43 (73%) achieved a CR and 6 (10%) a partial response (PR) for an ORR of 83%. One case (2%) showed stable disease (SD), while 8 patients (14%) progressed, and 1 (2%) was not evaluable for response. With a median follow-up of 16 months, the 2-year PFS and OS were 51% and 69%, respectively, without significant difference between relapsed and refractory patients. OS was higher for BeGEV-responding (CR+PR) patients compared with those who failed the induction regimen (2-year OS: 86% vs 0%, p CONCLUSIONS: This phase II study demonstrates that BeGEV is a highly effective salvage regimen able to induce a remarkable proportion of complete remission prior to ASCT in relapsed/refractory HL patients. These data provide a strong rationale for further development of the BeGEV regimen. Disclosures Luminari: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees.

Background American Society of Clinical Oncology guidelines recommend the use of growth factor after high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support. This randomized trial aims to demonstrate the noninferiority of pegfilgrastim (PEG) compared with filgrastim (FIL) after HDC. Patients and methods Eighty patients were assigned to FIL at a daily dose of 5 μg/kg or a single fixed dose of PEG (6 mg) 1 day after PBSC. The primary end point was the duration of neutropenia both in terms of absolute neutrophil count (ANC) 0.5 × 109/l. Results The mean duration of neutropenia was 6 and 6.2 days and the mean time to reach an ANC >0.5 × 109/l was 11.5 and 10.8 in the FIL and PEG group, respectively. No differences were observed in the mean time to reach an ANC >1.0 × 109/l (12.2 versus 12.0 days) in the incidence of fever (62% versus 56%) and of documented infections (31% versus 25%). The mean duration of antibiotic therapy was 5.7 and 4.0 days in FIL and PEG group, respectively. Conclusion PEG is not inferior to FIL in hematological reconstitution and represents an effective alternative after HDC and PBSC.

The purpose of this study was to analyse our experience of early discharge 2 days after high-dose melphalan (HDM) (Day-1) followed by peripheral blood stem cell re-infusion (Day-0) and re-admission on Day +5 in patients with hematological diseases or solid tumors. From 2000 to November 2005, seven patients received tandem Melphalan 200 mg/m(2) HDM with peripheral blood stem cells transplantation (PBSC-T), 130 a single HDM, for a total of 144 procedures. In 123 of them, patients were discharged on Day +1 for re-admission on Day +5 or earlier in the event of complications. Antibiotic prophylaxis was not used. Patients were hospitalised in positive-pressure reverse isolation room during the neutropenic period. Of the 123 procedures eligible for our mixed inpatient-outpatient management regimen, six (5%) required early re-admission for complications. Full engraftment was achieved in all cases. Median time to neutrophil count >0.5 x 10(9)/microL and >1 x 10(9)/microL were 12 and 14 days, respectively. Median time to platelet recovery (>20 x 10(9)/microL) was 13 days. Severe extra-hematological toxicities occurred in 78 (63%) patients: all had oral mucositis and five had associated diarrhoea. During hospitalisation, 94/123 (76%) experienced febrile neutropenia, 20/94 (21%) had documented infection and 74/94 (79%) were considered fever of unknown origin. Median fever duration was 1 day (range 0-11). Median duration of antibiotic treatment was 6 days (range 3-26). Median time to discharge (from Day 0) was 16 days (range 11-57). There was no mortality by on Day +100. Our experience of early discharge after HDM and PBSC-T with re-admission on Day +5 is safe and feasible with acceptable frequency of hematological and extra-hematological toxicities. The regimen allows reduced hospital stay and hence cost savings.

Our goal was to optimize use of granulocyte colony-stimulating factor (G-CSF) after high-dose chemotherapy and autologous peripheral blood stem-cell transplantation in lymphoma patients, limiting G-CSF administration to patients infusing a suboptimal CD34(+) cell number. Of 124 consecutive patients with histologically proven Hodgkin's and non-Hodgkin's lymphoma from January 2001 to June 2004, 60 patients (group 1) givenor = 5 x 10(6)/kg CD34(+) cells received no G-CSF; 64 patients (group 2) givenor = 5 x 10(6)/kg CD34(+) cells received G-CSF from day +5 after stem-cell reinfusion. The median times to reach 0.5 x 10(9)/L and 1.0 x 10(9)/L neutrophils were, respectively, 3 and 4 d shorter in G-CSF group and this difference was statistically significant (P = 0.0014; P = 0.0001). In terms of antibiotic and antimycotic requirements, gastrointestinal toxicity, days of hospitalization, and transfusion requirements, no differences were demonstrated between the two groups. No statistically significant difference was demonstrated for the total number of febrile episodes (52 for group 1; 53 for group 2; P = 0.623) and the median number of febrile days (2 d for both groups). Myeloid reconstitution values for both groups agree with published results for autotransplanted patients treated with G-CSF from 7 to 14 d. Also, major clinical events, antibiotic, antimycotic, and transfusion requirements, and hospital stay were similar to published findings. Our data suggest that G-CSF administration can be safely optimized, used only for patients infused with a suboptimal CD34(+) cell dose.

Introduction: XPO1 (CRM1, Exportin 1) is the sole transporter of many tumor suppressor proteins (including MYC, BCL2, BCL6, BTK, IkB) and is elevated in non-Hodgkin Lymphoma. Selinexor (Sel, KPT-330) is an oral covalent inhibitor of XPO1, the first clinical molecule of the Selective Inhibitors of Nuclear Export drug class. The phase I clinical trial of Sel in hematologic malignancies showed promising early single-agent efficacy with modest toxicity in relapsed Diffuse Large B-cell Lymphoma (DLBCL, Gutierrez et al, ASCO 2014). DLBCL, the most common lymphoid malignancy, is currently cured in only 10% of relapsed patients, and consists of 2 subtypes based on putative cell of origin (COO): activated B-cell (ABC) and germinal center B-cell (GCB). We performed preclinical studies of Sel, modeling its single-agent efficacy in frontline and relapsed DLBCL and its potential synergy with other clinically relevant therapeutics. Long-term follow-up data on patients(pts) treated with Radiolabeled antibody 90-yttrium-Ibritumomab Tiuxetan (RIT) are necessary to define the role of RIT-therapy (RIT-t) in current clinical practice. There are few reports about the use of RIT outside clinical trials. Outcome and toxicity of radioimmunotherapy remain a matter of concern. Incidence of MDS/AML reported after RIT-t as consolidation in front line varies from 3 to 4.3% (Czuczman et al, JCO 2007; Morschhauser et al, JCO 2012). A recent study with RIT and autologous stem cell transplantation (ASCT) as front line therapy in mantle cell lymphoma reported 20% incidence of secondary malignancies, (Arranz et al, Haemat 2013). So the aim of this study was to analyze the outcome of pts treated with RIT-t in clinical practice and to assess the incidence of secondary neoplasia particularly MDS/AML. We included in this retrospective analysis all pts with Diffuse B Large Cell Lymphoma (DBLCL), Follicular Lymphoma (FL) and Marginal Zone lymphoma (MZL), treated with RIT-t over the last decade at our Institution. We adopted the standard RIT therapeutic regimen: infusion of 250 mg/m2 rituximab on day 1, a second 250 mg/m2 dose on day 7, followed by dose of RIT (0.4 mCi/kg), administered 4 h following rituximab infusion. Response assessment was made as recommended by International Workshop criteria. Survival analysis was performed with Kaplan-Meier method and univariate analysis with Log-Rank test with a significance at 0.05. Between March 2006 and January 2014 61 pts underwent RIT-t, of these 57 had complete data and were considered for analysis. There were 16 DBLCL, 29 Follicular Lymphoma and 12 MZL. Twentythree were male, 34 female. Median age at diagnosis was 62 years(yrs) (range 36; 79), 66yrs (range 39;79) at RIT-t. Thirteen pts (all DBLCL) received RIT-t as front line consolidation. Forty-four pts (3 DBLCL, 12 MZL, 29 FL) underwent RIT-t after ≥1 therapy line: one prior line was received by 15pts, 2 by 19, 3 by 8 and 4 by 2. Before RIT-t 24pts were in relapse (2DBLCL, 2MZL, 20FL), 9 were refractory (2 MZL, 7 FL), 7 in partial response (1 DBLCL, 5 MZL, 1FL) while 4 were in complete remission (2 MZL, 2FL). Disclosures No relevant conflicts of interest to declare.

BACKGROUND AND AIMS: Hairy cell leukemia (HCL) is very sensitive to purine analogs (PAs), but ~40% of patients relapse and become progressively less responsive to these myelotoxic and immune-suppressive drugs. Having discovered the BRAF-V600E kinase-activating mutation as the genetic lesion underlying HCL (Tiacci et al, NEJM 2011;364:2305), we performed the first clinical trial of a BRAF inhibitor (vemurafenib) in refractory/relapsed HCL. In particular, this is a phase-2, academic, single-arm, Italian, multi-center (n=8) study (HCL-PG01; EudraCT 2011-005487-13). METHODS: In 11 months we enrolled 28 BRAF-V600E+ HCL patients, needing therapy due to cytopenias and including: i) 6 patients primary refractory to a PA; ii) 21 patients who relapsed early and/or repeatedly after PAs and had received a median of 4 previous therapies; and iii) a 81-year old patient showing severe myelotoxicicity after a PA (discouraging its further use). Previous treatments other than PAs included interferon, rituximab and splenectomy in 12, 14 and 8 patients, respectively. Complete remission (CR) required resolution of cytopenias (N≥1500/mmc, PLT≥100000/mmc, Hb≥11 g/dl), no morphological evidence of HCL cells in the bone marrow biopsy and blood smear, and no splenomegaly. Partial remission (PR) required resolution of cytopenias, and a ≥50% reduction of splenomegaly and of marrow and blood HCL involvement by immunophenotyping. Two patients were not evaluable as they went off-study after ≤1 week of treatment (due to drug-unrelated acute myocardial infarction and consent withdrawal after grade-3 drug-related reversible pancreatitis). RESULTS: Vemurafenib, given orally at the dose of 960 mg twice daily on an outpatient basis for a median of 16 weeks, was generally well tolerated. Drug-related adverse events (mainly arthralgias, skin toxicities, pancreatitis; no myelosuppression) were frequent, but reversible in all patients, and were typically grade 1-2. Only 7 patients developed grade 3 events, and none grade 4 events. Although we did not observe any cutaneous squamous cell carcinomas/keratoachantomas (as reported in BRAF-V600E+ melanoma patients treated with vemurafenib), 3 patients developed 2 basaliomas and 1 superficial melanoma, all treated with a simple excision. Notably, overall response rate was 96% (25/26 patients): 9/26 (34.6%) CRs and 16/26 (61.4%) PRs, obtained after a median of 8 and 9 weeks respectively. CR and PR patients included 1 and 5 primary refractory ones, respectively, as well as 4 and 10 not responding to the last prior treatment, respectively. In all CR patients immunohistochemistry showed minimal residual disease (≤10%) at the end of treatment. Six of 9 (67%) CR patients enjoyed normal blood counts at a median of 13 (range 12-15) months from the end of treatment (see Figure): 3 of these 6 patients showed no morphological evidence of HCL in the bone marrow biopsy (complying with a continuous CR) at 12, 13 and 15 months, respectively, whereas the other 3 lost the bone marrow CR status, all at 12 months. The remaining 3/9 CR patients (33%) developed a mild cytopenia (N ~1000/mmc or PLT ~80000/mmc) 5, 9 and 12 months post-treatment, respectively: in the 2nd patient the cytopenia remained stable until the last follow-up at 15 months, whereas in the other two cases it worsened requiring therapy 9 and 18 months post-treatment, respectively (see Figure). These two latter patients were recently retreated with vemurafenib for 12 and 4 weeks, and obtained a PR and a second CR. Among the 16 PR patients, 5 (31%) mantain normal blood counts at a median of 12 (range 8-17) months post-treatment (see Figure). The other 11 PR patients developed cytopenia(s) after 3 months of median follow-up (range 5-10): in 6 patients (38%) no anti-leukemic therapy was started at a median of 9 (range 6-12) months post-treatment, whereas in the remaining 5 cases (31%) cytopenia(s) worsened requiring therapy at a median of 8 (range 5-11) months of follow-up (see Figure). Four of these latter 5 patients were retreated with vemurafenib for 12 weeks: 3 cases had a minor response and the last one witnessed a second PR that lasted less than the first PR (3 versus 9 months). CONCLUSIONS: In heavily pre-treated HCL patients, a short oral course of vemurafenib was safe, and proved quickly and highly active. Retreatment with vemurafenib was able to reinduce remissions in patients relapsing after a CR, but was less effective in patients relapsing after a PR. Figure 1 Figure 1. Disclosures Off Label Use: Off-label use of vemurafenib in hairy cell leukemia will be discussed as part of a clinical research protocol..

Introduction The seminal phase 3 trial conducted by the German CLL Study Group demonstrated that the addition of the anti-CD20 monoclonal antibody [mAb] rituximab to the FC platform (FCR) improved response rates, progression free survival and also overall survival. However, FCR showed considerable hematologic toxicity, particularly among patients over age 70. Pentostatin demonstrated similar response frequency to other purine analogues in CLL. Furthermore, its relative lack of myelotoxicity has allowed to use it with improved tolerability particularly when administered in combination with myelotoxic agents such as cyclophosphamide. Ofatumumab is a fully human anti-CD20 mAb with clinical activity as a single agent in patients with fludarabine-refractory CLL. Ofatumumab appears to have greater single agent clinical activity than rituximab in patients with previously treated CLL and also has activity in rituximab-refractory patients. Given the reported efficacy of chemo immunotherapy [CIT] in CLL and the activity and toxicity profile of pentostatin combinations, we designed a trial of pentostatin, cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) aged ≥ 65 years and ECOG PS of 0-2 were enrolled to receive Pentostatin 2 mg/sqm and Cyclophosphamide 600 mg/sqm both as intravenous infusions at day 1 of each 21 day cycle and Ofatumumab administered as intravenous infusions (Cycle 1: 300 mg day 1 and 1000 mg day 2, subsequent cycles: 1000 mg at day 1). Ofatumumab premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was of 6 cycles. The primary endpoint was overall response rate (ORR) including detection of minimal residual disease (MRD) and secondary endpoints included, progression-free survival (PFS) overall survival (OS) and safety. Patients 49 patients from 12 centres from the italians regions of Lombardy and Piedmont were included. Baseline demographics were: Median age 72.8 years with 64% aged over 70, among them 32 were males (65%). Disease characteristics in 32 patients evaluable at this point were: 76% Binet stage B and 24% C; 45% of patients had unmutated IGVH, 7 % showed 17p deletions. Results ORR was 93.7% with 41% CR(11)/CR(2) with incomplete marrow recovery [CRi]. All six intended courses of treatment were administered to 30 (94%), and 90% of these patients received full-dose treatment. The reason for discontinuing treatment before completing six courses was myelosuppression occurring in 2 patients. The primary reason for dose reduction was again myelosuppression. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 62% of patients receiving PCO with the most common being neutropenia [Total number of patients with at least one Grade 3 or 4 event: 19 patients] while anemia and thrombocytopenia were detected only as grade 1 to 2 in 41% and 25% of cases respectively. Of the grade 1 to 2 toxicities, fever occurred in 2 patients (6%), hypotension occurred in 2 patients (6%), nausea and vomiting occurred in 3 patients (9%), skin rash of grade 1 occurred in 2 patients. Grade 3 infusion-related AEs were reported in 12% of patients. There were no grade 4 toxicities associated with any Ofatumumab infusion. Grade 3 infection was reported in 1 patient (3%) being a pneumonia. No deaths during treatment occurred in these 32 subjects. Conclusion Ofatumumab added to Pentostatin and Cyclophosphamide demonstrated clinically important results and is well tolerated in patients with previously untreated CLL. In this preliminary report the efficacy of this ofatumumab-based CIT compares favorably to the historical rituximab-based CIT using the same chemotherapeutic agents with a more manageable side effect profile in this older population. Further data in a higher number of enrolled patients and including MRD detection will be presented at the Meeting. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

Abstract 3652 Background Patients with classical Hodgkin lymphoma (cHL) who fail stem cell transplantation have very poor prognosis and new drugs with encouraging activity and low toxicity profile are required. Recently, Bendamustine has demonstrated efficacy as single agent in several hematological malignancies and it represents a suitable alternative for cHL patients. Methods Patients with relapsed/refractory cHL after high-dose chemotherapy and autologous or allogeneic transplant, were treated with Bendamustine as single-agent in 16 FIL Centers. Endpoints included overall response rate (ORR), adverse events and survival. All patients provided written informed consent at the time of treatment. This observational study was approved by Ethical Committees at all sites. Results From October 2007 to May 2012, 73 patients were included in a single-agent salvage program with Bendamustine. Of them, 69 were eligible for the analysis. Median age was 34 yrs (range, 21 – 63). Bendamustine was administered to cHL patients refractory to, or relapsing after autologous (n = 46) or autologous and allogeneic (n = 23) transplants. Forty-eight were refractory to previous treatment, whereas 21 were relapsed patients, including 11 early relapse (12months). Three dosages of Bendamustine were employed: 90mg/smq, 100mg/smq and 120mg/smq for 2 consecutive days every 28 days. The median number of administered cycles was 4 (range, 1 – 12). ORR was 58%, including 25% complete remission (CR) and 33% partial response (PR). Thirty-eight percent experienced progression and 4% had stable disease. Median time to response was 3.4 months (range; 1.4 – 10). Median duration of response was 5.1 months (range; 0.1 – 23). In multivariate analysis factors affecting the response are: refractory disease and more than 3 previous chemotherapy lines. With a median follow-up of 13 months (range; 1 – 32), median progression free survivals (PFS) was 10 months while median overall survival (OS) was not reached. The 1 and 2-year progression-free survival (PFS) were 50% and 24%, respectively (Figure 1). The 1 and 2-year OS were 71% and 68%, respectively (Figure 2). Bulky disease, ECOG>0 and lack of CR to Bendamustine have a negative impact on outcome in multivariate analysis. Dose-reduction was required in 22% of the patients with no impact on response (p 0.613). Twenty patients received GCS-F, mainly in the 120 mg/sqm cohort. Drug-related toxicity of any WHO grade was documented in 33/69(48%) of patients. Severe hematologic toxicity was observed in 20/69 pts (29%); grade 3–4 neutropenia, thrombocytopenia and anemia were observed in 11 (16%), 11(16%) and 4(6%)pts, respectively. Of note only one patient required drug discontinuation due to severe thrombocytopenia. Infection was the most common nonhematologic toxicity. Severe infections, mainly sepsis, occurred in 5pts but no one required drug discontinuation. Conclusion In our experience, Bendamustine is a useful single-agent with manageable toxicity for cHL patients with relapsed/refractory disease after autologous or allogeneic transplant. These results support prospective strategies with Bendamustine alone or in combination as pretransplant induction regimen. Disclosures: No relevant conflicts of interest to declare.

Abstract 1914 Introduction: Bendamustine has demonstrated efficacy as single agent in several lymphoproliferative disorders, including Hodgkin's lymphoma (HL). Despite the wide use of this compound, alone or in combination, there are no published data regarding its mobilizing activity. In 2011, we started a phase II open-label prospective study with Bendamustine, Gemcitabine and Vinorelbine (BeGEV) to evaluate the efficacy of this induction regimen before high dose chemotherapy plus autologus stem cell transplant (ASCT). One of the study objectives was to detect the role of Bendamustine as part of a mobilizing regimen for peripheral blood stem cell (PBSC) collection. Methods: Between August 2011 and July 2012, 16 consecutive patients with relapsed/refractory HL were enrolled in a Phase II open-label prospective study with BeGEV followed by ASCT. The treatment schedule was: Bendamustine (90mg/sqm, days 2–3), Gemcitabine (800mg/sqm, day 1 and 4) and Vinorelbine (25mg/sqm, day 1) plus G-CSF 10mcg/Kg beginning on day 7 continued daily until the target yield would be reached. PBSC collection was planned starting from cycle 1 or from cycle 3 in case of bone marrow involvement. Three million CD34+/Kg were considered as the minimum cell dose established for a safety rescue. Other than successful rate of harvest, we evaluated the absolute number of collected CD34+ cells/Kg, the number of procedures performed per cycle, preleukapheresis circulating CD34+ cells/mcL, white blood cells (WBC) count and the day of first collection. Adverse events were also recorded. All patients provided written informed consent at the time of study inclusion. Results: Of the 16 patients enrolled, 14 already underwent leukapheresis. All patients were able to mobilize readily and all achieved the primary end point with at least 3.6 × 10>6 CD34+/Kg collected in a single cycle. The median yield of CD 34+/Kg collected was 7.8 × 10>6 CD34+/Kg (range, 3.6–15) after a median of 1 procedure (range, 1–2). The median preleukapheresis circulating CD34+/mcL and WBC count/mcL were 76/mcL (range, 25–201) and 21750/mcL (range, 11200–87080), respectively. The median day of first collection was 12 (range, 9–15). Six pts underwent leukapheresis at cycle 1, 7 pts at cycle 2 (6 pts due to logistic reasons,1 to Cytomegalovirus reactivation). One pt underwent leukapheresis at cycle 3 for personal reasons obtaining the highest yield (15×10>6 CD34+/Kg). Hematologic and non-hematologic side effects were acceptable and no toxic deaths occurred. One patient developed blood-pressure decrement during the apheresis but she was able to complete the procedure without sequelae. To date, 6 patients (43%) underwent ASCT with prompt engraftment. Data about neutrophils and platelets engraftment will be presented in the final analysis. Comparison with historical IGEV published data (Magagnoli et al, BMT 2007) is reported in Table 1. Conclusions: This is the first prospective study evaluating Bendamustine as mobilizing agent in resistant HL pts before ASCT. Despite the small sample, our results show that BeGEV regimen, combined with G-CSF support, can be successfully and safely used to mobilize PBSC. Disclosures: No relevant conflicts of interest to declare.

Abstract 335 The cure of relapsed or refractory Hodgkin Lymphoma (HL) still remains a challenge. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care but almost half of patients relapse after ASCT and have poor outcome. Predictive factors including an interval from end of first line therapy to relapse shorter than 12 months, an Ann-Arbor stage III or IV at relapse, and relapse in previously irradiated field are currently used to identify patients with poor outcome. Development of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) assessment improves evaluation of response both in first line and salvage treatments. The aim of our study is first to confirm the predictive value of PET status before ASCT and then to compare ASCT strategy (single versus tandem) in patients with relapsed and/or refractory HL. We here report a series of 111 consecutive patients with relapsed and/or refractory HL who achieved at least partial remission (PR) at PET evaluation after one line of salvage chemotherapy and who underwent single or tandem ASCT. PET response assessment showed 85 (77%) patients in CR (PET- group) and 26 (23%) in PR (PET+ group). Five-year overall (OS) and progression free survival (PFS) were 81% and 64% respectively. There were significant differences in 5-year PFS (79% versus 23%, p Disclosures: No relevant conflicts of interest to declare.

Abstract 93 BACKGROUND. Positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) currently represents the mainstay for response assessment in HL, as defined by revised response criteria (Cheson, 2007). PET negativity is mandatory to define complete remission (CR), independently from the persistence of residual masses at computed tomography (CT scan). Nevertheless, some reports suggest a slightly worse prognosis among patients (pts) with CT scan residual masses. The aim of this study was to evaluate the unfavorable predictive value of residual CT scan masses in HL pts with PET negative at the end of treatment. MATERIAL AND METHODS. The present analysis was retrospectively conducted in 105 pts with negative PET at the end of first or second line treatment, at our institution, from February 2004 to February 2009. All pts had disease evaluation performed also with CT scan. RESULTS. Main clinical characteristics: median age 58 years, males 62, B-symptoms 25, bulky disease 41, prior radiotherapy 57. Seventy-four pts were evaluated after first line treatment program, while 31 pts after salvage therapy program. In 76 pts, residual CT scan mass (PET-/CT scan +) of at least 2.0 cm in the largest diameter was assessed. Fifty-seven had only one site residual mass, while 19 pts had more than one site. Considering the whole series, with a median follow-up of 45 months, 23 pts relapsed, nine patients died and 94 are alive without disease. The five year disease-free survival (DSF) for PET-/CT scan- vs PET-/CT scan+ pts was 89.4% and 68.7% respectively (P=0.053). The prognostic impact of residual mass at CT scan had a correlation with the dimension of the residual itself in a continuous fashion: the larger is the mass, the lower the DFS: HR 1.03 (1.01; 1.05) p 0.007. This difference is even more pronounced when a cut-off of 4 cm in the largest diameter of the residual mass is applied: in patients with a mass diameter ≥ vs < 4 cm, DFS is 50% vs 82% respectively (HR 3.25: CI 1.5; 7.04, p 0,029 – figure 1). Among all the other prognostic factors analyzed (number of masses, first vs salvage treatment program, sex, bulky disease, B-symptoms), no correlation with DSF or overall survival (OS) emerged. CONCLUSIONS. In our study we observe a significant difference in DFS among PET negative pts with or without CT scan residual masses after therapy for HL. This difference is more significant when the residual mass is larger than 4 cm. Thus, despite PET is the main tool in respons-e definition, CT scan maintains an important role and can not yet be abandoned. The role of consolidation radiotherapy in these cases should be focused. Disclosures: No relevant conflicts of interest to declare.