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Abstract 3956 Background: Recently in large randomized studies, the addition of Rituximab to standard chemotherapy in the first-line treatment of follicular lymphoma (FL) demonstrated improvements in long-term outcome in FL. Methods: We compared the outcome of 111 naive FL patients (pts) treated at our institution from 1995 to 2009 with a single alkylating agent in combination or not with Rituximab: 58 pts received Chlorambucil plus Rituximab (R-Chl) and 53 pts Chlorambucil and prednisone (Chl+PDN). The 2 schedules included an induction phase, where Chlorambucil was given at 6mg/mq for 6 consecutive weeks in both groups and the Rituximab in 4 weekly administrations. The maintenance phase was longer in the Chl+PDN group: Chlorambucil was administered 6mg/mq daily 14 days each month for a total of 12-months of treatment versus 14 days with monthly-Rituximab for 4 consecutive months in the R-Chl group. Results: The demographic and prognostic factors are reported in Table 1. At the end of treatment the ORR was 98% in the R-Chl pts and 77% in the Chl+PDN group, with a percentage of complete response of 79% and 55% respectively. No significant incidence of adverse events were reported and only one HBsAg positive patient in R-Chl group discontinued the therapy. One case of myelodysplastic syndrome was described in a Chl+PDN relapsed patient. With a median follow up of 34 months, the OS and the EFS in R-Chl pts is 95% and 76% respectively. Otherwise, with a median observation time of 82 months in the Chl+PDN group 73% are alive and only 28% of pts maintained the response. The median time to subsequent therapy (TTST) is 21 and 15 months respectively in the 2 groups. Conclusions: The addition of Rituximab to alkylating in first-line treatment in previously untreated FL pts improves significantly the EFS and prolongs the time to next antilymphoma therapy compared with alkylating alone. Because of its low toxicity profile, our combination with Rituximab and Chlorambucil could be considered a first-line therapy, especially in FL patients not eligible for aggressive chemotherapy regimens. Disclosures: No relevant conflicts of interest to declare.

Diffuse Large B-Cell Lymphoma (DLBCL) is the most frequent aggressive non-Hodgkin’s Lymphoma (NHL) in adults. Presently, prognostic stratification relies on clinical characteristics and International Prognostic Index (IPI) is currently the most useful tool to identify high-risk patients (pts). Positron Emission Tomography (PET) with fluorodeoxyglucose (18F[FDG]) has been used to assess chemosensitivity in Hodgkin’s lymphoma: we investigated the role of 18F[FDG]-PET as prognostic tool in DLBCL treated with a R-CHOP-like chemotherapy. Forty-two pts with newly diagnosed DLBCL treated in our Institute from February 2006 to February 2008 were enrolled in this prospective study. Median age was 59 years (range 24–80), seventeen pts were male (40%); bulky disease was present in 20 pts (48%). Stage was I–II in 18 (43%) and III–IV in 24 pts (67%); IPI was low in 20 pts, low-intermediate in 12 pts, high-intermediate in 5 pts and high in 4 pts. Twelve pts (29%) had a primary extranodal DLBCL. Pts were treated with 6 cycles of CHOP-like treatment, associated with Rituximab in all but one patient; cycles were repeated every 21 days. An interim 18F[FDG]-PET was performed after three cycles (interim 18F[FDG]-PET) and at the completion of treatment (18F[FDG]-PET6). Interim PET result did not change the planned treatment; response was assessed with 1999 Cheson’s criteria. Four pts received radiotherapy after chemotherapy. Overall, 36 pts obtained a complete response (CR), the remaining six pts failed to obtain a CR. Median follow-up was 15 months (range 5–31 months); eight pts relapsed, and six patients died, two of them in CR. Overall survival (OS) at 2 years was 78%, and event-free survival (EFS) at 2 years was 77%. Interim 18F[FDG]-PET was performed after a median interval from the last therapy of 13 days (range 3–21) and was negative in 28 pts (interval 12 days) and positive in 14 pts (interval 13 days). Six positive and two negative interim 18F[FDG]-PET pts relapsed: sensitivity was 75%, specificity was 76%, positive and negative predictive values were 43% and 93%, respectively. Overall, 18F[FDG]-PET6 was positive in eight pts and negative in 34 pts; six positive and two negative 18F[FDG]-PET6 pts relapsed: sensitivity was 75%, specificity was 94%, positive and negative predictive values were 75% and 94%, respectively. The EFS at 2 years in pts with negative interim 18F[FDG]-PET was 90%, in positive interim 18F[FDG]-PET pts was 55%, which resulted statistically significant at the univariate analysis (p=0.01), as well as 18F[FDG]-PET6 (p=0.00). In all relapsed pts but one a salvage therapy with intensified chemotherapy and autologous stem cells transplantation (ASCT) was planned: four pts progressed during treatment or shortly after ASCT, and in three pts treatment is still ongoing. Interim 18F[FDG]-PET was proposed as a prognostic tool in DLBCL. Our data showed that interim 18F[FDG]-PET was statistically associated with EFS, however, nine pts (64%) with a positive interim 18F[FDG]-PET obtained a CR after induction treatment, and eight of them (89%) did not relapse. Our findings do not support an early intensification of pts with DLBCL with a positive interim 18F[FDG]-PET because of the risk of overtreatment of a large part of these pts; however, we performed interim 18F[FDG]-PET after three cycles of therapy, and this could have influenced the results. A longer follow-up and a greater number of pts could be necessary to draw definitive conclusions.

In CLL/SLL pts the combination of purine analogue and rituximab represents a well known effective therapy. Human concentrative nucleotide transporter (hCNT1) and human equilibrative nucleotide transporter (hENT1) are proteins involved in uptake of nucleoside analogues into the tumour cells. The aim of this study was to investigate R-2CDA as first line therapy and in pre-treated pts with active CLL and SLL, and to identify, by pharmacogenomic approaches, genetic factors that may predict clinical response to such treatment. 45 pts with active CLL (27 pts) or SLL (18 pts) were treated. The median age was 59 years (31–76). Patients received 4 cycles of rituximab 375 mg/m2 on day 1 and 2-CDA 0.1 mg/kg (subcutaneously) on days 2 to 6. The treatment was repeated every 4 weeks. A CT scan of the abdomen was performed at baseline and at the end of treatment in all pts; CT scan before treatment was abnormal in 42 pts. Minimal residual disease was evaluated by 6-colour flow-cytometry and PCR methods. Treatment outcome was evaluated according to NCI-WG updating guidelines: to confirm a CR the marrow should be free of clonal B-CLL cells by flow-cytometry and a CTscan should be negative. At baseline we investigated, on bone marrow for SLL and on peripheral blood for CLL, the expression of human concentrative nucleotide transporter (hCNT1) and human equilibrative nucleotide transporter (hENT1) using ABI PRISM 7000 Real Time RT-PCR platform in 24 pts. 42 pts (26 untreated) were fully evaluable for response.LDH and beta2microglobulins were abnormal in 14% and 30% of pts respectively. The percentage of neoplastic cells in the bone marrow was more than 70% in 17% of pts. The overall response rate was 88% (26% CR and 62% PR), with 21% of untreated pts and 5% of pre-treated pts achieving a CR. Severe neutropenia (grade 4) developed in 7% of pts. 4 pts developed pneumonia, 1 with neutropenia. 1 pt had reactivation of herpes zoster virus and 1 pt experienced febrile neutropenia of unknown origin. The median TTP was 41 months. There was not statistically significant difference in terms of duration of response between untreated and pre-treated pts (TTP: 44 vs 35 months, p=0.1814). Pts achieving a CR had a longer response duration than pts with PR (p=0.0047). Low serum lactate dehydrogenase levels, a lower (< 70%) neoplastic marrow infiltration at baseline and a normal CT scan at the end of therapy (independent of response) predicted a longer response duration (p=0.0145, p=0.0164 and p=0.008 respectevely). The pharmacogenomic analysis showed a difference (p=0.8345) in terms of hCNT1 expression levels between patients achieving a CR and pts with PR or NR. Pts in CR had higher levels of hCNT1 expression and the increase of 1 unit of the expression level of hCNT1 is associated with a reduced risk of PD by 33%. The refractory pts had lower levels of hCNT1 than non refractory pts but the difference was not statistically significant. There was no statistically significant difference in terms of hCNT1 expression between CLL and SLL pts. The combination of 2-CDA and rituximab induces a high response rate, including CR in pre-treated pts. The treatment is well tolerated with acceptable toxicity also in pts over 70 years. The achievement of a CR is important to obtain durable response. The correlation between the levels of expression of hCNT1 and the response to therapy needs to be confirmed in larger studies.

Here we present the clinical results and the outcomes of 143 consecutive newly-diagnosed follicular lymphoma (FL) patients (pts) treated with 3 different modalities of treatment in our institution from 1994 until 2007. During this period, from 1994 to 2002, 55 pts received Chlorambucil and Prednisone (Chl+PDN), subsequently 31 pts Rituximab with Chlorambucil (R-Chl) and 57 pts a 4-weekly standard-dose of Rituximab alone (R). Chlorambucil was given in an induction phase at 10mg/day for 6 consecutive weeks followed by a longer maintenance phase in the first group: 2-week pulses of 10 mg daily with 2-week intervals for a total of 12-months of treatment versus four 2-week pulses with monthly-Rituximab. In the single agent R group 36 pts received maintenance with at least 4-bimonthly administrations. The 3 groups were comparable for demographic and prognostic factors: median age at diagnosis was 55 yrs, over 60% of pts were in advanced stages and mainly asyptomatic (about 90%) and over 50% of pts in each group were low-risk FLIPI. A third of pts in both Rituximab-based treatment groups had bone marrow involvement and bulky disease. In terms of ORR 78% of pts treated with Chl+PDN, 97% with R-Chl and 72% with R single agent, obtained a clinical response, with a percentage of complete response of 58%, 90% and 47% respectively. No significant incidence of adverse events were reported and none discontinued the therapy because of toxicity. One case of myelodysplatic syndrome was described in a relapsed patient of the Chl-PDN group. With a median follow up of 72, 56 and 27 months in the 3 groups evaluated, the CR rate was maintained in 29%, 74% and 37% of pts respectively with a median duration of response of 36, 40 and 24 months. Rituximab as first-line in FL pts seems safe, feasible and able to induce a high rate of clinical response similar to those achieved with standard chemotherapy alone. On the other hand, the immunochemotherapy seems to confirm its superiority in terms of response rate and duration of response.

Early stage HL patients (pts) benefit from a short course of chemotherapy combined with IF radiotherapy. In our previous experience six courses of VBM chemotherapy (Stanford regimen) were administered with IF radiotherapy. However, despite good clinical results, the schedule was modified in terms of total chemotherapy cycles delivered, in order to reduce the risk of long term toxicities. PET and CT scan were performed at staging to identify a low risk patients (pts) group. From May 2001 to November 2006, 32 treatment naïve Hodgkin’s lymphoma pts (18 male, 14 female) were treated with four courses of VBM chemotherapy (D1, 8: Vinblastine 6 mg/sm, Bleomycin 10 mg/sm, Methotrexate 30 mg/sm, repeated every 28 days) followed by IF radiotherapy. Median age was 37 years (range 16–73). Main histology was classical HL in 26 pts, while lymphocyte predominant was observed in 6 pts. Pts were all stage I-IIA (no bulky disease), no more than three sites involved, performance status 0–1 and ESR < 50. CT scans were performed before and after chemotherapy and radiotherapy. PET scans were performed before and after chemotherapy in 26 pts, and after radiotherapy if not performed before or in case of positivity after chemotherapy. Chemotherapy was usually well tolerated: three pts experienced G3-4 neutropenia while the main non- haematological toxicities recorded were G3 transaminitis in 3 pts and G1-2 neuroconstipation/abdominal pain in 18 pts. IF radiotherapy was performed one month after the last chemotherapy cycle; median dose administered was 30Gy (range 26–30.4). At the end of chemotherapy 7 pts were PET positive. While one patient developed progressive disease, the other six pts became negative after radiotherapy and are still in complete remission (CR). 29 pts (90%) completed the whole program obtaining a CR. Two pts progressed before radiotherapy, while one patient shifted to an anthracycline containing schedule after two cycles due to stable disease. With a median follow-up of 42 months (range: 7–73), all pts are alive. 1 out of 29 CR pts progressed and is now receiving intensive chemotherapy program with autologous stem cell transplant. In our experience four cycles of VBM chemotherapy combined with IF radiotherapy is an effective program. Furthermore this regimen that doesn’t contain alkylating agents or anthracyclines avoids alopecia and decreases the risk of long term toxicity. PET scan effectively helps to identify low risk early stage HL pts that can take advantage of this therapeutic approach.

Mantle cell lymphoma (MCL) is an aggressive disease, currently incurable with standard-dose chemotherapy. Autologous cell transplantation (ASCT) is frequently considered a therapeutical approach in MCL, despite not generally being curative. In controlled studies upfront ASCT showed a significant event-free survival advantage, that might be improved by the addition of the anti-CD20 monoclonal-antibody (MoAb) (Rituximab®) in the myeloablative regimen. Based on these evidences, we prospectively analysed our patients (pts) affected by MCL, who received a continuous Rituximab administration in course on treatment. From May 2000 to the present we treated 22 pts with histological diagnosis of MCL, including 16 pts (73%) newly diagnosed. The majority were male (15/22) and the median age at diagnosis was 56 years old (range 35–66). Disease was stage III–IV: 21 pts with bone marrow involvement in 60%. Eleven pts presented extranodal involvement. The induction schedule included 2–4 CHOP-like regimen with MoAb (R-ACOD), followed by mobilization chemotherapy with cyclophosphamide, MoAb and G-CSF. Harvest was performed successfully in all pts with a median number of CD34-positive cells of 8.0 x 106/Kg (1.9–22.8 106/Kg). Subsequently the pts received 2 cycles of high-dose, cytarabine-based regimen with MoAb (R-ESHAP). Rituximab injections were given at standard dose (375 mg/mq). Before ASCT, 11 pts (50%) were in complete response (CR); in particularly 5 of them who were pretreated. Eight achieved partial response, while one was in progression. Two pts were not restaged. One patient did not undergo ASCT, because of serious pulmonary infection after high-dose cytarabine. In terms of conditioning regimen all pts received Rituximab (375 mg/mq), Melphalan (180mg/mq) in association with either Idarubicin (15mg/mq for 3 days) in 13 pts and or Novantrone (60 mg/mq for 1 day) in 8 pts. After stem cell reinfusion and G-CSF from Day +5, the median time to recovery (neutrophil counts >0.5x103) was 14 days (range 13–28 days) in the first regimen versus 10 days (range 8–11 days) in the more recent regimen. During aplasia the infection rate was low, as a matter of fact we observed just two episodes of pneumonia, that resolved at neutrophil recovery. No toxic death was reported. Response at 3 months after ASCT was evaluable in 19 patients (90%); one was lost at follow-up, while one has been transplanted one month ago. Seventy patients (80%) achieved complete response, maintained in 11 of them after a median time of 23 month (range 10–79) after ASCT; seven of them were in complete response before the transplant procedure. With a median time of 27 months (range 9–46 months) 7 patients progressed and 4 of these died because of lymphoma. Our study supports that ASCT can be considered a valid approach to induce high response rate. To enhance the ASCT outcomes, the addition of Rituximab can be considered a feasible approach associated with its “purging in vivo” effect. Long-term disease control might be reflected upon a plateau in the survival curve, but a randomised study and longer follow up is warranted.