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Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.

Patients who develop severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (alloSCT) have a higher risk for invasive fungal infection (IFI). At our center, fluconazole prophylaxis is standard and upfront mold-effective prophylaxis performed only in patients with specific risk constellations. A total of 290 patients undergoing alloSCT between May 2002 and August 2011 were analyzed. Patients were regarded as high-risk if they suffered from acute GvHD II-IV° or extensive chronic GvHD. The 2-year incidence of an IFI after alloSCT was 8.97% (26/290) in the entire cohort and 7.78% (7/90) in the high-risk group. Mortality due to IFI was 3.85% (1/26) without including a high-risk patient. In the multivariate analysis a pre-transplant fungal infection was the only significant risk factor for developing an IFI after alloSCT (HR = 5.298; p = .001). A fluconazole prophylaxis in patients with GvHD after alloSCT is feasible in facilities with HEPA filtration and high awareness of clinical signs for IFI.

Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in theIn a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients withWith a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rankSorafenib maintenance therapy reduces the risk of relapse and death after HCT for

Objectives Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan-drug resistance to available antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections. Methods We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis. Results The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P = .012), with a positive trend observed for treatment regimens that included voriconazole (P = .054). Conclusions Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development.

Objectives Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. Methods We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. Results Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%–85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%–51%, p 0.053). In Kaplan–Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). Conclusions While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

PURPOSE Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene ( FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD–positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD–positive AML.

Patients with acute myeloid leukemia (AML) and a

Background: The StiL NHL1-2003 trial demonstrated that Bendamustine-Rituximab (B-R) is a highly effective treatment for patients with WM achieving a median PFS of 69.5 months. Rituximab (R) maintenance is part of a standard treatment for follicular lymphoma. In WM, however, the role of R maintenance is unclear. In this study we compared the effect of 2 years R maintenance vs. observation after first-line treatment with B-R in patients with previously untreated WM. Methods: Patients needed to have advanced stage of disease with indication for treatment (e.g. B-symptoms, anemia, hyperviscosity syndrome, etc.). Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity. All patients were treated with up to 6 cycles of B-R plus 2 additional R cycles. Only patients responding to B-R were randomized to either R maintenance (q 2 months for 2 years) or observation. Results: Of 293 registered patients, 5 were excluded due to lack of data and other reasons. Median time of follow-up was 70.2 months at the time of this analysis (July 2019). 257 of 288 patients with a median age of 67 years were evaluable for response evaluation. The median baseline value of IgM was 31.3 g/l, and of Hb 10.1 g/dl. Median PFS for all patients (intention to treat) was 78.0 months. The median OS was not yet reached, with an estimated 5-year-survival of 78%. A total of 38 secondary malignancies were recorded, with 1 AML during observation and 1 MDS in R maintenance. 235 patients (91.4%) responded to B-R induction, with the majority of patients (231, 89.9%) achieving a partial remission. Of 218 randomized patients, 109 (50%) were randomized to R maintenance and 109 (50%) to observation. Median age of randomized patients was 67 years, patient characteristics were comparable for both groups. The 2-year R maintenance provided a better disease control with a median PFS of 101 months in the R maintenance group compared to the median PFS of 83 months in the observation group, however, this difference was not statistically significant with a hazard ratio of 0.80 (95% CI 0.51 - 1.25, p = 0.32). The median PFS of the group of all patients receiving treatment with B-R induction only was 65.3 months and is consistent with the results of the previous StiL NHL1-2003 trial (69.5 months). This group of 179 patients includes both non-randomized patients (B-R non-responder, not randomized for any reason) and patients randomized to observation. There was no difference in OS with the median not yet reached for both R maintenance and observation. Conclusions: We confirmed that induction with B-R is a highly effective treatment for WM. After a median observation time of 5.9 years the results could not demonstrate an improvement in PFS or OS after a 2-year R-maintenance when compared with observation after B-R induction in patients with WM. Disclosures Rummel: Sandoz: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche Pharma AG: Honoraria, Research Funding. Hensel:Roche: Honoraria, Other: travel expenses. Buske:Hexal: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau; Amgen: Research Funding. Schmidt:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Hexal: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees. Willenbacher:IQVIA: Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; European Commission: Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria. Dürig:Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Barth:Takeda: Honoraria; Lilly Pharma: Honoraria; Roche: Honoraria; Medac: Honoraria; Hexal: Honoraria. Hinke:Roche: Honoraria. Greil:Genentech: Honoraria, Research Funding; Eisai: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Boehringer Ingelheim: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sanofi Aventis: Honoraria; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria.

Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation. Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients. In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients. We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection.

Introduction. The prognosis of patients with follicular lymphoma (FL) has improved during recent years following the introduction of immuno-chemotherapy and Rituximab maintenance. Nevertheless, some patients still relapse early and have a poor prognosis. Several prognostic scoring systems have been developed using clinical, laboratory as well as molecular data, while the early identification of high-risk patients remains a challenge. In this context, the relevance of circulating bcl2/IgH levels for patient stratification is not clear. We could show that high circulating bcl2/IgH levels in the peripheral blood (PB) before therapy were an independent adverse prognostic factor for progression free survival (PFS) in patients receiving R-CHOP or Bendamustine-Rituximab (B-R) in the NHL1 study of the German StiL group (Zohren et al, Blood 2015). Methods. Using a sensitive quantitative PCR method as previously described (Zohren et al, Blood 2015), a total of 2,491 circulating bcl-2/IgH level analyses were performed on PB samples before (n=415) and after (n=305) 6 cycles first-line immuno-chemotherapy and during follow-up (n=1,771). Results of these molecular studies were correlated with clinical outcome. We first present a 10-year update of the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial. Secondly, we report the results from the StiL-NHL7-trial including bcl2/IgH analyses of 308 bcl2/IgHpositive patients who received B-R and Rituximab maintenance. Results. With a median follow-up of 10 years in the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial, high PB bcl-2/IgH levels (bcl-2/IgH to reference gene (tPA) ratio >1) before treatment as compared to low (ratio In contrast, among the 308 bcl-2/IgHpositive patients of the StiL-NHL7-trial, who all received B-R and Rituximab maintenance, PB bcl-2/IgH levels (ratio >1 vs When comparing StiL-NHL1 and StiL-NHL7 patients with respect to bcl-2/IgH levels and the effect of Rituximab maintenance, we found that Rituximab maintenance led to a significantly better PFS. In patients with low (ratio 1) bcl-2/IgH levels (22 vs 99 months, HR 3.46, 95% CI 1.93-6.20; p Conclusion. High circulating bcl-2/IgH levels in the PB before first line therapy identify a subgroup of patients with advanced FL who have significantly shorter PFS after standard immuno-chemotherapy. These patients greatly benefit from the addition of Rituximab maintenance, because pre-treatment bcl-2/IgH levels lose their predictive value with Rituximab maintenance therapy. On the other hand, patients who remain bcl-2/IgHpositive after standard immuno-chemotherapy have short PFS and OS despite treatment with Rituximab maintenance and therefore are candidates for experimental treatment approaches. Disclosures Kobbe: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Zohren:Pfizer Inc.: Employment. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Greil:Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Symbio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

7515Background: Rituximab (R) maintenance is part of a standard treatment for follicular lymphoma. In MZL, however, it is not yet common practice. In this study we compared the effect of 2 years of...

7501 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p < 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.

Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or MCL and was presented at ASH 2009, ASCO 2012, and published in The Lancet in 2013. The final published analysis at a median follow-up of 45 months demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group, compared to the CHOP-R group (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.44–0.74; p Methods: 549 pts with indolent lymphomas or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: 514 randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. Fewer pts treated initially with B-R needed second-line treatments due to disease progression compared to CHOP-R treated pts: 93 pts (36%) in the B-R group received salvage treatment compared with 140 pts (55%) in the CHOP-R group. Of those in the CHOP-R group, 69 pts (49%) received B-R as salvage. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.53, 95% CI 0.40-0.68; p The difference in complete response (CR) rates (independent of treatment arms) between male (n=272, median age 63 years) and female (n=242, median age 64 years) pts was statistically significant: 28.6% for male pts versus 42.1% for female pts (p=0.0016). Female pts had a longer median TTNT compared to male pts (not yet reached vs. 52.2 months, respectively; HR 0.70, 95% CI 0.54-0.90; p=0.006). The achievement of a CR was associated with significantly prolonged OS, with an estimated 10-year survival rate of 72.6% for pts with a CR and 63.6% for pts with a partial response (p=0.006). The difference in OS between the treatment arms was not statistically significant, with 65 and 76 deaths in the B-R and CHOP-R arms, respectively. The estimated 10-year survival rates were 67.4% for B-R and 60.1% for CHOP-R (p=0.262). In pts with indolent lymphomas (total group without MCL), there was a trend toward longer survival for the B-R group compared with the CHOP-R group, with 43 deaths out of 215 pts (20.0%) in B-R and 58 deaths out of 205 pts (28.3%) in CHOP-R. The estimated 10-year survival rates for pts with indolent lymphomas were 71.9% for B-R and 61.5% for CHOP-R (HR 0.70, 95% CI 0.48-1.04; p=0.076). No difference in OS was found in the subgroup of pts with MCL (n=95) (HR 1.28, 95% CI 0.69-2.39; p=0.429). Twenty sNPL were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R) to date. Updated sNPL results will be presented at the ASH meeting. Conclusions: In pts with previously untreated indolent lymphomas, and in elderly pts with MCL, B-R demonstrates a PFS and TTNT benefit over CHOP-R. OS for the entire group of patients was not significantly different while treatment with B-R resulted in a trend toward survival benefit in the group of pts with indolent lymphomas. Disclosures Off Label Use: Indication and dosage of bendamustine.

Introduction: Fludarabine plus rituximab (F-R) is an established treatment option for patients (pts) with relapsed/refractory follicular lymphoma (FL), other indolent lymphoma, or mantle cell lymphoma (MCL). To further improve the treatment in this setting we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of bendamustine plus rituximab (B-R) versus F-R for pts with relapsed FL, other indolent lymphomas or MCL. Patients and Methods: 230 pts 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 case of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and complete response rate (CR). 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: A total of 219 pts were evaluable for the analysis (114 B-R; 105 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, 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; 25.3% F-R). 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; Waldenström’s Macroglobulinemia, 11.9% and 11.1%; MCL, 20.2% and 21.2%; other indolent lymphomas, 23% and 20.2%. A median of 6 cycles were given in both treatment arms, with 75.2% and 53.4% of B-R and F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2014), the median observation time was 96 months. The ORR was significantly higher with B-R than with F-R (83.5% vs. 52.5%, respectively; p< 0.0001). The CR rate with B-R was also significantly higher than that with F-R (38.5% vs. 16.2%; p=0.0004). Median PFS was significantly prolonged with B-R compared with F-R (34 vs. 12 months; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.38–0.72; 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). 17 pts (14.9%) developed a secondary neoplasia after B-R compared with 16 pts (15.2%) after F-R. Of these, 5 pts in the B-R group, and 3 pts in the F-R group developed a secondary hematological neoplasia (2 AML [1 AML M4], 1 CML, 1 DLBCL, and 1 HD after B-R; and 2 AML M4, and 1 MDS after F-R). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.38, 95% CI 0.32-0.71; p=0.0003) and PFS (HR 0.35, 95% CI 0.31-0.62; 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 validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: B-R was more effective than F-R in this setting of relapsed FL, other indolent lymphomas and MCL due to higher overall and complete response rates, a longer PFS, and an improved OS. These data confirm the high anti-lymphoma activity of B-R. Disclosures Off Label Use: Indication and dosage of bendamustine.

Introduction: Factor XIII (FXIII) is a coagulation factor, playing an important role in the coagulation process by keeping the hemostatic clot and allowing tissue repair. The incidence of FXIII deficiency in acute leukemia is not well characterized. FXIII deficiency is known to have a high bleeding risk and cannot be detected by lab evaluation of aPTT and/or INR levels. In combination with thrombocytopenia in patients (pts) presenting with acute leukemia, FXIII deficiency increases bleeding risk (for example in invasive procedures or for intracranial hemorrhage). In 2013 a study was conducted in 9 pediatric pts (6 acute leukemias, 1 burkitt, and 2 solid tumors) in whom FXIII deficiency was found. These pts had bleeding complications that were resolved by FXIII concentrate substitution (Wiegering. V. et al. Haematologica, June, 10, 2013).Patients affected from AML and ALL could easily be screened at diagnosis regarding FXIII level. In the setting of newly diagnosed acute leukemia pts in whom thrombocytopenia is frequently occurring, a preemptive substitution of FXIII could be considered in order to reduce the risk of bleeding complications. Methods: In this retrospective analysis (Jan. 2009 to June 2014) we identified a total of 103 ptspresentingwithnewly diagnosed acute leukemia in whom we assessed FXIII level. In 95 pts FXIII level was available at initial diagnosis of acute leukemia and during treatment. Substitution of FXIII concentrate have been used in case of factor’s deficiency below 70% (normal range 70%-130%). Results: Patients presented withAML (64 primary AML and 20 secondary AML), or ALL (10), or 1 AUL. Median age was 67 years (range: 25-95). Thirty-four pts (35.8%) were younger than 60 years, 61 pts (64.2 %) were older than 60 years. FXIII deficiency was found in 35/95 pts (36.8%) with a median level of 49% (range: 21%-68%). Of those 35 pts with FXIII deficiency 33 had AML (1 AML M0, 9 AML M1, 2 AML M1/2, 5 AML M2, 6 AML M4, 5 AML M5). All pts (5/95) with AML M3 showed a deficiency with a median level of 28%. A level below 70% could be found in 7 out of 13 FLT3-ITD positive pts (53.8%) and in 7 out of 24 NPM1 positive pts (29.2 %). Median FXIII level was 34% for FLT3-ITD positive pts, respectively 30% for NPM1. FXIII substitution in deficient pts was well tolerated and effective. No patient showed intracranial hemorrhage. In addition, invasive procedures like bone marrow biopsy and central line insertion were possible without clinically relevant bleeding complications. In responding pts achieving remission following chemotherapy, a trend towards higher concentration of factor XIII during treatment was observed. Conclusions: Patients affected by AML or ALL are presenting usually with thrombocytopenia and have a high bleeding risk. In case of FXIII deficiency, risk of bleeding is increased potentially leading to a higher leukemia-related morbidity and mortality. Detection of FXIII deficiency is an established method and routinely available. Substitution of FXIII decreases the risk of bleeding and can reduce leukemia associated morbidity and mortality. In our study FXIII deficiency occurred in more than a third of our pts, including all AML M3 patients. We found a trend for more FXIII deficiency in FLT3-ITD high risk group patients. We suggest screening at diagnosis and during treatment of all acute leukemia pts and FXIII substitution in case of deficiency. To evaluate further the role of FXIII assessment and substitution in case of FXIII deficiency in acute leukemia, a prospective trial should be considered. Disclosures No relevant conflicts of interest to declare.

Background Cyto- and molecular-genetic abnormalities evaluated at initial diagnosis are the most powerful prognostic and in part also predictive markers in acute myeloid leukemia (AML) with regard to achievement of complete remission (CR) and survival. Nonetheless, after relapse the prognostic impact of clinical characteristics and genetic abnormalities assessed at initial diagnosis with respect to achievement of subsequent CR and survival are less clear. Aims To evaluate the probability of CR achievement and survival in relapsed AML patients in correlation to clinical characteristics and genetic abnormalities assessed at initial diagnosis as well as treatment strategy. Methods The study includes intensively treated adults with newly diagnosed AML enrolled in 5 prospective AMLSG treatment trials between 1993 and 2009. Patients with acute promyelocytic leukemia were excluded. All patients received intensive therapy, including allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) during first line therapy. Results A total of 3218 patients (median age, 54 years; range, 16-85 years) were enrolled in 5 AMLSG treatment trials. Of these, 1307 (41%) patients (16-60 years, n=958; ≥61 years, n=349) experienced relapse, n=194 after alloHSCT, n=75 after autoHSCT and 1038 after chemotherapy. Salvage strategies were as follows: (i) n=907, intensive chemotherapy (INT) followed in n=450 by HSCT (matched related donor [MRD], n=114; matched unrelated donor [MUD], n=303; cord blood graft [CB], n=3; haplo-identical family donor [HID], n=18; autoHSCT, n=12); (ii) n=100, direct alloHSCT (MRD, n=31; MUD, n=63; HID, n=4) or n=2 autoHSCT (TPL); (iii) n=29, donor lymphocyte infusions (DLI) in patients after alloHSCT in CR1; (iv) n=60, demethylating agents/low-dose cytarabine (NON-INT); (v) n=24, experimental treatment within phase I/II studies (EXP); (vi) all other patients (n=187) received best supportive care (BSC). After salvage therapy CR rate was 38% and after the different treatment approaches as follows: INT, 37%; TPL, 73%; DLI, 38%; NON-INT, 8%; EXP, 29%. After failure to respond to INT, n=159 additional patients achieved a CR2 after HSCT resulting in an overall CR2 rate of 50%. A logistic regression model revealed CEBPA double-mutant (dm) (OR, 6.42; p=0.0001), core-binding factor (CBF) AML (OR, 2.87; p=0.0002), a direct HSCT strategy (OR, 3.32; p=0.0002), and mutated NPM1 (OR, 1.59; p=0.02) as favorable (only if response after HSCT was included) and FLT3-ITD (OR, 0.66; p=0.04), age (difference of 10 years; OR, 0.82; p=0.003), NON-INT (OR, 0.08; p=0.0001) and in trend a previous alloHSCT in CR1 (OR, 0.65; p=0.08) as unfavorable independent parameters for achievement of CR2. Median follow-up for survival after relapse was 4.3 years and survival after 4 years was 22% (95%-CI, 19-25%). Patients proceeding to alloHSCT after first relapse (n=536; MRD, n=145; MUD, n=366; HID, n=22; CB, n=3) had a 4-year survival of 36% (95%-CI, 32-41%) and those not proceeding to alloHSCT of 8% (95%-CI, 6-11%). In univariable analyses the combined genotype mutated NPM1 in the absence of FLT3-ITD (p=0.66) was not associated with a favorable outcome. A multivariable regression model including alloHSCT as a time-dependent co-variable revealed alloHSCT performed after relapse (HR, 0.34; p Of 561 patients achieving CR2, 252 experienced 2nd relapse (REL2) and 114 died in CR2. Most REL2 patients (n=117) received INT whereas n=54 received BSC only. Allo- and autoHSCT were performed in 55 and 3 REL2 patients, respectively. CR3 rate in patients who received treatment was overall 40% including response to HSCT of 58%. Conclusions Patients with relapsed AML have an overall probability of less than 50% to achieve a CR2 and CR3 after intensive salvage chemotherapy; the only exceptions are AML with CEBPAdm and CBF-AML. AlloHSCT either as direct treatment of relapse or as salvage therapy after failure of intensive chemotherapy may overcome chemo-resistance. Disclosures: Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees.

Abstract 2739 Background: Bendamustine-rituximab (B-R) has demonstrated substantial efficacy in the primary treatment of indolent lymphomas. A multicenter prospective randomized trial was initiated to investigate the impact of adding rituximab maintenance following B-R first-line induction. The trial included patients (pts) with Waldenström's Macroglobulinemia (WM), marginal zone, small lymphocytic and mantle cell lymphomas. Here we present first and preliminary results for pts with WM. Methods: Treatment consisted of a maximum of 6 cycles of B-R (bendamustine 90 mg/m2, rituximab 375 mg/m2) administered every 28 days plus 2 cycles of rituximab every 4 weeks. Responding pts (≥ PR) were eligible for further treatment and were randomized to observation or 2 years of rituximab maintenance every two months. The primary endpoint is PFS. Results: From April 2009 to July 2012, 57 centers included a total of 162 pts with newly diagnosed WM with a median age of 67 years (31% < 60 years, 69% > 60 years). At baseline/inclusion/screening, the median values for b2-microglobulin (b2M), hemoglobin and IgM were 3.3 mg/L, 10.1 g/dL and 2110 mg/dL (max. 13400 mg/dL), respectively. To date (Aug 2012) 116 pts are evaluable for response (43 women [37%] and 73 men [63%]). 100 pts have responded to B-R leading to an overall response rate (ORR) of 86%. At the time of response evaluation, the median Hb was 12.6 g/dl and the median IgM was 380 mg/dl. 90 pts have undergone randomization to date, 43 to observation and 47 to maintenance. Randomization is ongoing. No results can be reported from that ongoing part of the trial. No uncommon toxicities were observed during B-R induction. Conclusion: Initial results of our trial confirm that for patients with Waldenström's macroglobulinemia, treatment with B-R is an efficacious treatment with a manageable safety profile. The role of rituximab maintenance in this disease is under investigation. Disclosures: No relevant conflicts of interest to declare.

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 1982 Background: Consolidation with 2 cycles of 25 mg lenalidomide and/or maintenance treatment with a dosage of 10–15 mg lenalidomide after high-dose therapy (HDT) and autologous stem cell transplantation (SCT) improves event-free survival (EFS) in patients with multiple myeloma (MM), as has been shown recently by two randomised clinical trials in the US and France with patients up to the age of 70 and 65, respectively. So far data on longer consolidation treatment and different dosages in the maintenance setting is lacking. Methods: In the randomized, open label phase III LenaMain trial (clinical trials gov: NCT00891384) patients up to the age of 75 years are treated with six cycles of lenalidomide consolidation at a full dosage of 25 mg starting three months after first-line treatment with HDT and autologous SCT. After consolidation patients receive maintenance treatment with either lenalidomide 5 mg or 25 mg, both until disease progression. Here we present data of an interim safety analysis of the consolidation phase of the study. The trial is conducted in 4 transplant centers in Germany und plans to enrol 194 patients. Enrolment started in April 2009, and interim safety analysis was conducted in September 2011 with the first 68 patients enrolled and 50 patients finishing the consolidation phase. Myeloma subtype was IgG, IgA, others in 55, 23, 23% of patients, respectively, who had a median age of 64 years (range 37–73) and an ISS stage of I in 50%, II in 27% and III in 23% of cases at the time of diagnosis. All patients were treated with a median of 3 (range: 1–6) cycles of induction treatment followed by cytotoxic stem cell mobilisation with cyclophosphamide (4g/m2) and HDT and autologous SCT. Thirty-seven patients younger than 66 yrs received conditioning with melphalan 200 mg/m2, which was repeated in 7 patients not achieving at least a very good partial response. Tandem-HDT with melphalan 100 mg/m2was used for 32 patients older than 65 yrs. A median of 113 days (range:56–153) after the last HDT, consolidation treatment with lenalidomide 25 mg daily for 21 days of a 28 days cycle was initiated. All patients received aspirin for prevention of deep-vein thrombosis. Results: Response rates at baseline 3 month after HDT for sCR, CR, vgPR, PR, MRSD, PD were 0%, 14%, 53%, 31%, 2% and 0%, respectively. Three patients developed an early relapse during the six cycles of consolidation therapy. After cycle 6 of consolidation treatment response rates for sCR, CR, vgPR, PR, MRSD, PD were 10%, 16%, 41%, 24%, 2% and 7%, respectively. The remission status was improved in one third of patients. After 6 cycles of consolidation treatment 4 patients had discontinued treatment due to AEs, 2 patients withdrew consent and sudden death of unknown cause occurred in one patient during cycle 1. A lenalidomide dosage of 25 mg for 6 cycles could be applied to 53% of patients. Dose reductions were necessary in 47% of patients. Lenalidomide dosage after cycle 6 was 20 mg, 15 mg, 10 mg and 5 mg in 21%, 6%, 15%, and 2% of patients, respectively. The most common hematologic AE was neutropenia (Grade 1–2 in 42%, Grade 3–4 in 39%). Anemia (Grade 1–2: 88 %, Grade 3–4: 3%) and thrombocytopenia (Grade 1–2: 67 %, Grade 3–4: 7 %) occurred less frequently. No bleeding AE was documented. Infectious complications were seen in 59% of patients including 7% with Grade 3–4. Non-hematologic toxicity was low, and Grade 3–4 AEs included pain (2%), skin symptoms (2%), and neurological and constitutional symptoms (7%). There was no statistically significant difference in toxicity and tolerated dosage between patients younger or older than 65 years. Conclusion: Dose-escalation with lenalidomide 25 mg for 6 cycles as consolidation treatment was very well tolerated and the toxicity was consistent with published data with lower lenalidomide exposure. This was also true for patients aged 66–75 who did not experience an increased toxicity. Lenalidomide 25 mg for six cycles appears to be an effective consolidation treatment, with approximately one third of patients improving their response status. Disclosures: Fenk: OrthoBiotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide is not approved for maintenace treament of patients with myeloma. Giagounidis:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kröger:Celgene: Research Funding. Schroeder:Celgene: Travel support Other. Kobbe:OrthoBiotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 415 Background: Alteration of DNA methylation, a hallmark of epigenetic modification, is currently discussed as one important pathomechanism in leukemogenesis. Using a next-generation sequencing approach, a frameshift mutation of the gene encoding the DNA methyltransferase (DNMT3A) in an acute myeloid leukemia (AML) case was identified. DNMT3A catalyses the addition of a methyl group to the cytosine residue of CpG dinucleotides, thereby affecting promoter methylation status and gene expression. Subsequent sequencing analysis in an independent cohort of 288 AML patients (pts) revealed DNMT3A mutations (DNMT3Amut) in 22% of the pts; mutations were associated with intermediate-risk cytogenetics and poor outcome. Aims: To evaluate frequency and clinical impact of DNMT3Amut in pts with AML aged 18 to 61 years who were treated within AMLSG treatment trials AML HD98A (Schlenk et al., J Clin Oncol 2010;28:4642–8) and AMLSG 07–04 (NCT00151242). Methods: DNMT3A mutation analysis was performed in 1218 AML (HD98A, n=685; AMLSG 07–04, n=533; de novo AML, n=1102; s-AML, n=45; t-AML, n=69) using a DNA-based PCR assay for all coding exons (1 to 23) followed by direct sequencing. The median follow-up was 5.06 years. Results: DNMT3A mut were found with an overall frequency of 19.6% (239/1218); 189 mutations were located in the MTase domain clustering at amino acid R882 (79%). All but one mutation were heterozygous; only 4 cases had two mutations. DNMT3A sequence alterations included 17 frameshift, 4 nonsense, and 222 missense mutations. DNMT3A mut pts were significantly older (P=.01), more frequently females (P=.001), had higher white blood cell and platelet counts (both P DNMT3A mutational status did not impact complete remission (CR) rate, event-free (EFS) and relapse-free survival (RFS), neither in the whole cohort (P=.09, P=.98, P=.11; respectively) nor in the subgroup of CN-AML (P=.39, P=.79, P=.19, respectively). DNMT3Amut had a negative impact on overall survival (OS) in trend in the whole cohort (P=.07) and significantly in CN-AML (P=.02). In multivariable analyses, DNMT3Amut were in trend associated with a negative prognostic impact on OS (hazard ratio, 1.24; P=.06). In addition, we performed subgroup analyses according to (1) the NPM1 mutational status, and (2) the molecular risk groups of CN-AML (as defined by the European LeukemiaNet classification). DNMT3Amut did not impact OS in NPM1-mutated patients in the whole cohort as well as in CN-AML (P=.34; P=.22; respectively), while in NPM1-wildtype patients DNMT3Amut were associated with inferior OS in both, the whole cohort and in CN-AML (P=.001; P=.005; respectively). In molecular unfavorable CN-AML (NPM1-wildtype with or without FLT3-ITD, NPM1-mutated with FLT3-ITD, CEBPA-wildtype), DNMT3Amut were significantly associated with worse OS (P=.002) compared with DNMT3A-wildtype pts, even outweighing FLT3-ITD as an unfavorable prognostic marker. There was no effect of DNMT3Amut in molecular favorable-risk CN-AML. Conclusions: DNMT3A mutations are confirmed as frequent genetic aberrations in AML, associated with normal karyotype, NPM1, FLT3-ITD, and IDH1/2 mutations. DNMT3Amut predicts for inferior outcome in molecularly-defined subsets of AML, that is, NPM1-wildtype AML and molecular unfavorable CN-AML. As a single marker, DNMT3Amut only had a moderate effect on outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 2679 Poster Board II-655 Introduction: Bendamustine, a hybrid alkylating agent, shows a unique mechanism of action with a good toxicity profile in various hematological malignancies, particularly in non-Hodgkin's lymphoma. Bendamustine (B) in combination with Rituximab (R) was demonstrated to be an effective regimen in first- or second-line treatment of patients (pts) with indolent lymphomas. So far, however, no data about the capacity of peripheral blood stem cell (PBSC) mobilization or a possible stem cell toxicity of B has been studied. It is still an open and clinically relevant question, if pts treated with B are able to mobilize enough stem cells for subsequent high dose therapy with autologous stem cell support. Objective: We performed a prospective randomized multicenter phase-III trial to compare the efficacy and safety of the combination of Bendamustine plus Rituximab (B-R) versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Chemotherapy was given in 6 cycles each (B: 90 mg/m2 d1+2). One of the secondary objectives (not mandatory) of this study was to evaluate the possibility to mobilize a sufficient number (at least 2.0 × 10E6 CD 34+ cells/kg) of PBSC and progenitor cells in younger pts after completing either B-R or CHOP-R and to compare both stem cells yields. Results: 549 pts have been randomized, 513 pts (B-R = 260, CHOP-R = 253) are evaluable. In each arm, 23 PBSC mobilizations have been performed. In the B-R as well as in the CHOP-R arm each 18 mobilizations were performed directly after completion of therapy, and in 5 pts stem cells were collected at the time of first relapse. Patient characteristics: initial bone marrow involvement was observed in 17 of 23 pts in the B-R arm and 14 of 23 pts in the CHOP-R arm, respectively. Median patient age was 51 years (B-R) and 53 years (CHOP-R). The mobilization regimen was either high dose cyclophosphamide + G-CSF (9 pts in each arm) or G-CSF alone in 7 pts after B-R and in 2 pts after CHOP-R, respectively. Alternative regimens such as Dexa-BEAM, DHAP, ICE and others were also used in the remaining patients. The median CD34+ cell-count/kg was not significantly different in the two arms with 4.55 × 10E6 CD34+ cells/kg (range 1.68 – 12.35) in the B-R group and 6.17 × 10E6 CD 34+ cells/kg (range 1.68 – 20.39) in the CHOP-R group, respectively. In both arms the medium number of apheresis to achieve these yields was not different (B-R: 1.85 vs. CHOP-R: 1.66). Only 3 pts were not able to mobilize at least 2.0 × 10E6 CD 34+ cells/kg: 1 patient after B-R (1.68 × 10E6 CD 34+ cells/kg), and 2 pts after CHOP-R (1.68 × 10E6 CD 34+ cells/kg, and in 1 patient no mobilization was possible). In patients who were mobilized directly after completion of first-line chemotherapy (18 pts in each arm), again, no differences (B-R: median 5.52 × 10E6 CD 34+ cells/kg vs. CHOP-R: median 7.35 × 10E6 CD 34+ cells/kg) were observed. The yield of stem cells in each 5 pts of both arms who were mobilized at the time of first relapse was also nearly the same (B-R: median 8.79 × 10E6 CD 34+ cells/kg vs. CHOP-R: median 7.3 × 10E6 CD 34+ cells/kg). Conclusions: Our results demonstrate that the collection of sufficient numbers of PBSC after B-R treatment is possible and appears to be comparable to the PBSC yield after prior treatment with CHOP-R. Disclosures: Rummel: Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding.

Recent reports have demonstrated the feasibility of using the anti-CD52 antibody Campath-1H for in vivo T-cell depletion (TCD) in the context of a fludarabine/melphalan-based reduced-intensity conditioning regimen (Kottaridis et al. Blood 2000, 96:2419). Major disadvantage of this protocol is the severe immunosuppression which results in an increased rate of opportunistic infections and disease relapses. Donor lymphocyte infusions (DLI) are frequently used to overcome this limitation. The application of DLI, however, is associated with a profound risk of GvHD. Depletion of CD8+ lymphocytes from either the allotransplant or from DLI has proven feasible to reduce the incidence of GvHD (Nimer et al. Transplantation 1994, 57:82; Giralt et al. Blood 1995, 86:4337). We set up a phase-I allotransplantation study which combines the Campath-1H (100mg)/fludarabine (150mg/m2)/melphalan (140mg/m2) preparative regimen with the preemptive administration of CD8-depleted DLI in patients with hematological malignancies not eligible for myeloablative conditioning. After early withdrawal of CsA immunosuppression, CD8-depleted DLI are scheduled in a dose-escalating regimen starting on day +60 after HLA-identical sibling transplantation and on day +120 after unrelated donor transplantation, respectively. For CD8-depletion of donor leukaphereses a new CliniMACS-based protocol using clinical grade CD8 Microbeads is used. Our data show that this procedure is efficient in reducing the content of CD8+ T-cells by at least 2.5 to 3.5 logs, while CD4+ cells remain largely unchanged. In this ongoing study, 8 patients (4 myeloma, 2 CMPD, 1 ALL, 1 NHL) were included and received peripheral blood stem cells (PBSC) from HLA-identical sibling (1), HLA-matched (5) or DRB1-mismatched unrelated donors (2), according to high-resolution HLA typing. Chimerism analyses on total bone marrow-derived cells as well as on purified CD4, CD8, CD19, CD14 and CD15-positive peripheral blood cells showed durable complete donor chimerism in all but one patient (see below). After successful withdrawal of CsA, 2 patients already received CD8-depleted DLI without any acute toxicity. In the first patient (UPN 3), who was transplanted from an HLA-identical sibling, DLI were given on days 60 and 120 (1 and 5 x 106 CD4+ T cells, respectively). The second patient (UPN 4), who was transplanted from a matched unrelated donor, received the first dose of 1 x106 CD8-depleted DLI on day 120. DLI were regularly followed by a more than 2-fold increase of CD4+ cells during the first two weeks after application, while CD8+ cells remained unchanged. After the second DLI, patient UPN 3 developed a grade 2 GvHD of the skin (d+22 after DLI). Both patients were at high risk for CMV reactivation (donor: CMV negative, host: CMV positive) and repeatedly received preemptive treatment. Immediately prior to the second DLI, the CD8+ cell count in patient UPN 3 increased during an ongoing CMV reactivation. Line-specific chimerism analysis revealed that more than 50% of these CD8+ cells were of host origin. As expected, transfer of CD8-depleted DLI from CMV-negative donors was unable to entirely prevent CMV reactivation in seropositive patients. Nevertheless, our preliminary data suggest that the preemptive transfer of CD8-depleted DLI is able to accelerate immune reconstitution after reduced intensity TCD allogeneic PBSCT without rapid increase of CD8+ donor cells.