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Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335.

To assess the influence of pretransplant cytoreductive therapy with special reference to interferon-alpha (IFN-alpha) treatment on major endpoints of allogeneic bone marrow transplantation (BMT), we studied 133 consecutive patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in first chronic phase who received marrow grafts from HLA-identical family (n = 103) or alternative donors (n = 30) at a referral-based transplant center. Fifty of these patients (38%) were previously exposed to IFN-alpha for a median duration of 14 months (range, 1 to 61 months), whereas 83 patients (62%) exclusively received hydroxyurea and/or busulfan therapy between 1 and 129 months (median, 15 months) pretransplant. Using the categorized treatment duration with each pretransplant cytoreductive agent as a measure for individual patient exposure to each agent, prolonged ( > 12 months) IFN-alpha administration was identified as the sole significant pretransplant therapy-related predictor of transplant outcome by proportional hazards regression analysis. The adjusted risk ratio (RR) of transplant-related mortality (TRM) was 2.5-fold higher (95% confidence limits [95% CL], 1.4 to 4.5; P < .004) compared with other pretransplant therapy and this was mainly attributable to a 3.1-fold higher RR (95% CL, 1.4 to 6.4; P < .005) of fatal posttransplant infections after prolonged IFN-alpha treatment pretransplant. Marrow graft failure developed exclusively among 7 of 30 patients (23%) with donors other than HLA-identical family members and was further restricted to patients who had been previously exposed to IFN-alpha. The probability of graft failure was 49% +/- 28% in 17 patients pretreated with IFN-alpha compared with 0% for the other 13 patients with mismatched family or unrelated donors (P < .008). In addition, a significant delay in neutrophil and platelet count reconstitution was observed among patients with donors other than HLA-identical family members after pretransplant IFN-alpha exposure. No influence of pretransplant cytoreductive therapy on either acute and chronic graft-versus-host disease or leukemic relapse was detected in this study. As a consequence of its adverse effect on TRM, prolonged pretransplant IFN-alpha treatment was independently associated with a 2.5-fold lower likelihood (95% CL, 1.4 to 4.5; P < .003) of 5-year overall survival and with a 2.3-fold lower likelihood (95% CL, 1.3 to 4.2; P < .004) of 5-year disease-free survival postransplant after adjustment for other significant prognostic factors in multivariate analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Interferon (IFN) therapy has become widely used for the treatment of chronic myelogenous leukemia. Hematologic remissions can be induced in about 60% of patients. Moreover, in a small number of patients loss of the Philadelphia (Ph) chromosome and of the BCR-ABL rearrangement is observed. We have used genomic Southern blotting as well as a two-step polymerase chain reaction (PCR) method to score for BCR-ABL messenger RNA (mRNA) in patients with hematologic remission induced by treatment with IFN alpha-2b alone or in combination with IFN gamma. Concomitantly, cytogenetic analysis was performed. In 11 of 115 patients reported here, a complete loss of rearranged BCR fragments was observed in Southern blots of peripheral blood (PB) and/or bone marrow (BM) cell samples. Malignant marker bands disappeared first in the PB. In six patients, this genotype remained stable, whereas in five patients, low-intensity, rearranged bands reappeared despite continuation of treatment. The reappearance of the malignant marker was not accompanied by a clinical relapse. Ph-negative metaphases were observed in PB cells of four patients and in the PB and BM cells of two of these patients. In the samples of the other patients, residual Ph- positive cells were detected. By two-step PCR, residual BCR-ABL rearranged transcripts were found in samples of 10 patients.

Abstract 2724 Background: The NHL 1 study, a prospective, multicenter, randomized, phase 3 study which compared B-R and CHOP-R as first-line treatment in indolent lymphomas and mantle cell lymphoma (MCL), demonstrated a significant benefit in progression-free survival (PFS) as well as improved tolerability for B-R compared with CHOP-R. Here we present an analysis of the impact of response quality on outcome. Methods: 514 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. Results: The overall response rate in the 514 pts (261 B-R; 253 CHOP-R) was 92.7% and 91.3% in the B-R and CHOP-R arms, respectively (as presented at the last ASCO meeting, J Clin Oncol 30, 2012 (suppl; abstr 3). A complete response (CR) was observed in 39.8% in the B-R arm and in 30% in the CHOP-R arm (p=0.021). The achievement of CR was associated with a significantly prolonged PFS and overall survival (OS) (Table 1). Analysis by treatment arm revealed a trend for superior PFS and a significantly improved OS for patients achieving CR following treatment with B-R. In the CHOP-R arm, patients in CR had a significantly superior PFS compared to those in PR with a trend to superior OS. Regardless of the quality of response, PFS was superior with B-R versus CHOP-R: For patients in CR, the median PFS was not reached with B-R, whereas for CHOP-R it was 53.7 months (p=0.0204). In patients achieving PR, treatment with B-R resulted in a median PFS of 57.2 months, and this was 30.9 months with CHOP-R (p=0.0002). We noted a statistically significant difference in CR rates between male (n=272, median age 63 years) and female (n=242, median age 64 years) patients. The CR rate was 28.6% in male patients and 42.1% in female patients (p=0.0016). Female patients had a longer median PFS (51.4 months) compared to male patients (38.6 months), however, this difference was not statistically significant (p=0.0866). Conclusions: Patients in CR following first-line treatment in our study had a significantly longer PFS and OS compared to those achieving a PR. Therefore, our results strongly suggest an association between quality of response and outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 856 Introduction: Promising results have been observed in two phase II studies evaluating the combination of bendamustine plus rituximab (B-R) in patients (pts) with relapsed/refractory follicular, other indolent or mantle cell lymphomas (MCL) (Rummel et al. JCO 2005; Robinson et al. JCO 2008). Fludarabine plus rituximab (F-R) is an established treatment option in this setting. Therefore, we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of B-R versus F-R for pts with relapsed follicular (FL), indolent or MCL. Patients and methods: 219 pts with relapsed FL, indolent or MCL in need of treatment were randomized to rituximab 375 mg/m2 (day 1) plus either bendamustine 90 mg/m2 (days 1+2) or fludarabine 25 mg/m2 (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however in cases of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: 11 pts were not evaluable due to protocol violations, and were not followed further. A total of 208 pts were evaluable for the final analysis (109 B-R; 99 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, International Prognostic Index (IPI), follicular IPI (FLIPI), bone marrow infiltration and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R and 25.3% F-R, respectively). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular 45.9 % and 47.5%, respectively; immunocytoma 11.9% and 11.1%; MCL 20.2% and 21.2%; other indolent lymphomas 23% and 20.2%. A median number of 6 cycles were given in both treatment arms, with 75.2% of B-R pts and 53.4% of F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2010), the median observation time was 33 months. Median PFS was significantly prolonged with B-R compared with F-R (30 vs 11 months; hazard ratio [HR] 0.51, 95 % confidence interval [CI] 0.34–0.67; p There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4 and 22.2%, respectively). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.21, 95% CI 0.22–0.67; p=0.0008) and PFS (HR 0.27, 95% CI 0.27–0.59; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R), compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw some validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: These data confirm the efficacy of B-R in pts with relapsed FL, indolent or MCL, and, in this setting, demonstrate a superior PFS benefit for this regimen in comparison with F-R. Disclosures: No relevant conflicts of interest to declare.

Abstract 3090 Introduction: Long term survival among patients (pts) with low grade/indolent Non-Hodgkin lymphoma (iNHL) is increasingly common, and as a consequence, a consideration of potential therapy-related sequelae, such as secondary neoplasia (sNPL), is of particular importance. Bendamustine plus rituximab (B-R) is an effective treatment option with a favorable toxicity profile in pts with iNHL. However, no data have been reported concerning later, therapy-associated complications with B-R. The aim of this study was to determine the incidence of therapy-related myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and solid tumors after B-R, in comparison with other anti-lymphoma chemotherapy regimens, in pts with follicular (FL), other indolent or mantle cell lymphoma (MCL). Patients and methods: Data for this analysis were obtained from 2 randomized studies, including a total of 697 pts: 1) StiL-study NHL-1, comparing B-R (bendamustine 90 mg/m2, d1+2, rituximab 375 mg/m2, d1; q 28 days) with CHOP-R (q 21 days) as first-line therapy in 513 pts (260 B-R, 253 CHOP-R) (median age 64 yrs, range 31–83); 2) StiL-study NHL-2, comparing B-R with F-R (fludarabine 25mg/m2, d1–3, rituximab 375mg/m2, d1; q 28 days) in 184 pts (median age 68 yrs, range 38–87) with relapsed disease (96 B-R, 88 F-R). Patients in this NHL-2 study had received a median of 1 prior therapy (range 1–7). Result: At the time of this analysis (May 2010), the median observation time was 35 months for NHL-1 pts and 33 months for NHL-2 pts. Most pts in both studies received 6 cycles of therapy. In the NHL-1 study, 16 pts (6.2%) developed sNPL after B-R as first-line treatment, compared with 19 (7.5%) after CHOP-R. Most (87.5%) sNPL were solid tumours: 4 gastrointestinal, 4 urothelium, 2 prostate, 2 squamous epithelium, 1 bronchial, and 1 adrenal after B-R; 6 gastrointestinal, 5 prostate, 3 bronchial, 2 breast, 1 melanoma, 1 urothelium, and 1 endocrinal pancreas after CHOP-R. The rate of secondary hematological NPL did not differ between arms; 1 MDS and 1 T-cell-lymphoma after B-R, 1 AML and 1 Hodgkin lymphoma after CHOP-R. The median time from initiation of study therapy to diagnosis of sNPL was 18.5 months for B-R, and 14 months for CHOP-R. 5 pts in the B-R group, and 2 in the CHOP-R group received additional chemotherapy after completing study therapy, and before diagnosis of sNPL. In the NHL-2 study, 6 pts (6.3%) developed sNPL after B-R as relapse therapy, compared with 9 (10.3%) after F-R (p=0.42). Of these, 3 pts in the B-R group, and 2 pts in the F-R group developed a secondary hematological NPL (2 MDS, 1 Hodgkin lymphoma after B-R; 2 AML/MDS after F-R). Solid tumors were observed in 3 pts following B-R (2 urothelium, 1 squamous epithelium), and in 8 pts following F-R (3 squamous epithelium, 2 bronchial, 1 gastrointestinal, 1 urothelium, 1 anal). The median time from initiation of study therapy to diagnosis of sNPL was 33 months for the B-R group and 24.5 months for the F-R group. Conclusion: This ongoing evaluation shows comparable rates of secondary MDS/AML and other sNPL between B-R and CHOP-R or F-R. This observation, combined with data from other studies showing improved efficacy with B-R compared with CHOP-R or F-R, confirm the value of B-R as a treatment option in patients with follicular, indolent or MCL. Longer follow-up of the patient cohorts reported here will provide important additional information on the rate of sNPL with B-R compared with other anti-lymphoma regimens. Disclosures: No relevant conflicts of interest to declare.

Abstract 441 Introduction: By means of standard chemotherapy advanced stage follicular lymphoma (FL) is an incurable disease. Clinical courses are characterized by a continuous tendency to relapse caused by residual neoplastic cells. Quantitative polymerase chain reaction (qPCR) to detect lymphoma cell that carry the t(14;18) translocation is a suitable method to measure minimal residual disease (MRD) in patients with FL. Despite several reports dealing with MRD qPCR in FL, its role in the clinical management of patients is still not clearly defined. Therefore, we carried out a multicenter study, to assess the prognostic value of sequential quantitative MRD detection in first-line treatment of FL using an improved version of a LightCycler based qPCR specific for the major breakpoint region (MBR) positive IgH/bcl2 translocation, provided by Roche Diagnostics® (Penzberg Germany). Patients and Methods: We analysed 718 blood (PB) samples of 179 patients with newly diagnosed FL treated within the multicenter randomized trial NHL1, conducted by the German StiL group (Study group indolent Lymphomas), comparing 6 cycles of R–CHOP versus R–Bendamustin (R-B). Samples were taken at diagnosis, after 6 cycles of either R–CHOP or R–B immuno-chemotherapy and every three months during follow-up. All samples were analyzed in the department of Hematology at Heinrich-Heine University in Duesseldorf. Results: At diagnosis, 112 out of 179 patients (62.6%) were positive for IgH/bcl2 within the MBR in the peripheral blood. Significantly higher amounts of bcl2/IgH positive cells were found in patients with bone marrow infiltration (p=0.012) and depending on the number of lymphatic nodes (LN) with disease involvement (>3 LN p=0.003; >5 LN p=0.0009; >7 LN p=0.022). Overall, a remarkable inter-individual variation of bcl2/IgH positive cells in the PB at diagnosis, reflected by ratios from 0.000281 to 81, was found. The estimated event free survival (EFS) at 2 years of patients who presented at diagnosis low to normal amounts of bcl2/IgH positive cells in the PB (ratio < 2, n=83) was 82% (SE 0.045), which was significantly better than the 47% (SE 0.11) observed in patients showing the highest amount of bcl2/IgH positive cells (ratio >2, n=24) in the PB (p=0.003). By univariate and multivariate analysis, we found that the amount of bcl2/IgH positive cells in the PB at diagnosis (p=0.001) as well as the achievement of a negative MRD status after therapy (p=0.0001) were significant predictors for relapse free survival. Monitoring of MRD levels before and after therapy revealed that 6 cycles of immuno-chemotherapy significantly reduced the amount of bcl2/IgH positive cells in the PB compared with pre-treatment MRD levels (p=0.0001; median bcl2/IgH/tPA ratio: before treatment 0.0734, range: 0.000281–81, after treatment negative, range: negative–0.17). After treatment, 86% of the patients (n=82) achieved a molecular remission in the PB defined as qPCR negative, whereas 14% (13 patients) remained PCR positive. Not reaching a molecular remission in the PB at the end of therapy had a significant negative influence on PFS. After a median follow-up of two years, patients who remained MRD positive in the first measurement after therapy had a significant lower PFS than MRD negative patients (p=0.0001; 9 months vs. not reached). There was no significant difference in the degree of tumor cell depletion in the PB induced by the two different regimens. So far, 539 follow-up samples from 3 up to 39 months after therapy were analyzed. Patients with a consistent negative MRD status throughout follow-up showed a trend towards longer PFS. After 38 months follow-up, MRD positive patients had a PFS of 54% compared to 78% in the group of MRD negative patients (p=0.066). Conclusion: QPCR for the t(14;18) performed at diagnosis and during follow-up on PB samples predicts treatment response and long-term clinical outcome of patients with FL. Disclosures: Zohren: Roche: Honoraria, Research Funding. Rummel:Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Kobbe:Roche: Research Funding.

Abstract 405 Introduction: Promising results have been observed in two phase-II studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas (Rummel et al., JCO 2005; Robinson et al., JCO 2008). In order to further investigate the role of the combination B-R we initiated a multicenter randomized phase-III study in October 2003 to compare efficacy and safety of B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for patients with follicular (FL), indolent and mantle cell lymphomas (MCL). Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine 90 mg/m2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement did not statistically significant differ between both arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76,9% in BR and 77,5 in CHOP-R) and stage III (19,2% in B-R and 18,6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol. Results: Of the 549 pts 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 × DLBCL, 3 × CLL, 2 × MM, 1 × HD, 3 × solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these 9 pts were not evaluable for response evaluation: 4 pts (3 × CHOP-R, 1 × B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT). A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93,8% vs 93,5%, respectively). The CR rate was significantly higher with 40,1% for B-R compared to 30,8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54,8 months for B-R versus (vs) 34,8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40,7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33). CHOP-R treatment was more frequently associated with serious adverse events (SAE) (n=49 in B-R vs n=74 in CHOP-R). Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10,7% vs CHOP-R 46,5%; p Conclusions: In this final analysis the combination of Bendamustine plus Rituximab improves PFS and CR rates while showing a better tolerability profile. These promising results suggest that B-R does have the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Disclosures: Rummel: Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Maschmeyer:OrthoBiotech: .

Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003, we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). The trial was calculated to power the study to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. The study is closed according to the planned recruitment schedule. Results: 546 patients have been randomized. For this second interim analysis, 437 patients are evaluable for response (B-R: n=221; CHOP-R: n=212). Median patient age is 64 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 41% for B-R compared to 33% for CHOP-R. The median follow-up time for both groups is 28 months. Thus far, 50 deaths have been observed (B-R: 25; CHOP-R: 25). Progressive or relapsed disease has been documented during the follow-up period: 58 in pts treated with B-R and 75 in the CHOP-R group. The median EFS for B-R is not yet reached, the median EFS for CHOP-R is 39 months with no statistical significant difference for the EFS between both groups. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (0% with B-R vs. 89% CHOP-R) and a lower number of infectious complications (number of patients with infections of any grade were 56 (25%) in the B-R group vs. 78 (37%) in CHOP-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 36% CHOP-R treated pts compared with 19% in pts treated with B-R, while in the CHOP-R group more frequently G-CSF was used. Conclusions: In this second interim analysis, the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. Further updated results will be presented at this time.

Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003 we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). A sample size of 474 pts were calculated to power the study sufficiently to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. Results: So far 439 patients have been randomized. 273 patients are evaluable for response for this first interim analysis (B-R: n=139; CHOP-R: n=134). Median patient age is 63 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 51% for B-R compared to 40% for CHOP-R. The median observation time for both groups is 17 months. Thus far, 15 deaths have been observed (B-R: 7; CHOP-R: 8). Progressive or relapsed disease has been documented during the follow-up period: 27 in pts treated with B-R and 32 in the CHOP-R group. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (40% CHOP-R vs. 0% with B-R) and a lower number of infectious complications (41 in CHOP-R pts vs. 19 in the B-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 41% CHOP-R treated pts compared with 12% in pts treated with B-R. Conclusions: In this first interim analysis the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. The study will be closed in December 2007 according to the planned patient recruitement schedule. Updated results will be presented at this time.

The BCR gene on chromosome 22 has received increasing attention because of its involvement in the Philadelphia (Ph′) translocation. For most restriction enzymes, this locus has been found to be nonpolymorphic. Two alleles have only been found when Taql-digested DNA is hybridized to a 5′ bcr-specific probe. We describe another two-allele polymorphism detected by the same probe in PvuII-digested DNA. The polymorphism is characterized by an additional PvuII site in the bcr region: this causes the appearance of an additional band of about 2.3 kb or 2.5 kb besides a 4.8-kb fragment in hybridizations with the 5′ bcr or a 3′ bcr probe. The incidence of the second allele is very low. It has only been found in some patients with hematopoietic malignancies and in a group of volunteers having a leukemia patient in their families.