Abstract: Purpose Although minimal residual disease (MRD) is an established surrogate marker for outcomes following treatment with chemoimmunotherapy, less is known about the value of MRD in chemotherapy-free treatments in the first-line setting. We investigated the prognostic value of MRD detection after a fixed-duration treatment of venetoclax plus obinutuzumab (VenG) with respect to clinical and genetic risk factors and source of material in previously untreated patients (pts) with CLL and coexisting conditions. Methods In this multinational, open-label, Phase 3 trial, 432 previously untreated pts with a Cumulative Illness Rating Scale score & gt;6 and/or an estimated creatinine clearance & lt;70 mL/min were randomized 1:1 to receive chlorambucil or venetoclax (216 pts per treatment group) until completion of cycle 12, and in combination with obinutuzumab for the first 6 cycles. The primary endpoint was progression-free survival (PFS), MRD was a secondary endpoint. Peripheral blood (PB) samples for MRD were taken at cycle 7, 9, and 12, and then serially every 3 months. In pts with a treatment response, MRD in bone marrow (BM) was assessed at cycle 9 and 3 months after end of treatment (EOT). MRD was analyzed by quantitative immunoglobulin allele-specific real-time (IGH-ASO)-PCR (cut-off: 10-2 and 10-4) and additionally by next-generation sequencing (NGS, Adaptive Clonoseq assay, cut-off: 10-4, 10-5 and 10-6). Outcome was analyzed according to known MRD risk groups i.e. detectable (≥10-4) and undetectable ( & lt;10-4) as well as to known clinical and biological risk factors. Landmark PFS and time to MRD re-detection from EOT were analyzed using Kaplan-Meier methodology. Apart from re-detection to MRD level ≥10-4, pts with a competing event (including progression of disease, relapse, new CLL therapy, and death) also counted towards the MRD re-detection events total. Results On the basis of the intention-to-treat population (i.e. for the full trial population and irrespective of sample availability), VenG achieved higher rates of undetectable MRD at EOT compared with chlorambucil and obinutuzumab (ClbG) (PB: 75.5% vs. 35.2%, BM: 56.9% vs. 17.1%). In contrast, detectable MRD in PB was found in 19 (8.8%) VenG pts and 103 (47.7%) ClbG pts. Of these, 11 (5.1%) VenG vs. 47 (21.8%) ClbG pts had intermediate MRD at ≥10-4- & lt;10-2 and 8 (3.7%) vs. 56 (25.9%) pts had high positive MRD at cut-off 10-2. Of the 19 VenG pts with detectable MRD, 64.3% had unmutated IGHV, 22.2% had a TP53 disruption and 17.6% had a complex karyotype. In pts with undetectable MRD in PB, the rate of complete response at EOT was higher with VenG than with ClbG (55.8% vs. 40.8%, Table 1). Achieving undetectable MRD in PB with VenG was associated with a high proportion of patients with corresponding BM clearance of 74.8% with only 4.9% of pts being BM MRD-detectable. In addition, depth of MRD response measured by NGS was more profound in VenG compared to ClbG ( & lt;10-5: 67.6% vs. 19.9%, & lt;10-6: 42.1% vs. 6.5%) with undetectable MRD according to both NGS and IGH-ASO-PCR at cut-off 10-4 in 74.5% of pts treated with VenG and an overall concordance between both methods of 95.4%. Considering pts with undetectable MRD in PB at EOT, the time to MRD re-detection was longer with VenG than with ClbG (median 17.7 months and 34 (20.9%) re-detection events with VenG vs. median 7.5 months and 55 (72.4%) re-detection events with ClbG, HR 0.192, 95% CI 0.124-0.296). In landmark analysis from EOT, undetectable MRD correlated with favourable PFS rates at 24 months as compared with detectable MRD: 89.1% vs. 61.9% in VenG and 93.9% vs. 32.6% in ClbG, respectively. Median PFS was not reached in undetectable MRD groups (Figure 1a). Further landmark analysis of PFS by MRD status showed that undetectable MRD translated into improved PFS regardless of the clinical response status at EOT (Figure 1b). Conclusion Fixed-duration treatment with VenG achieves unprecedentedly high and sustainable rates of undetectable MRD in patients with previously untreated CLL and coexisting conditions. Findings confirm the prognostic value of MRD assessment at EOT for this chemotherapy-free treatment regimen. Due to high concordance of undetectable MRD in PB and BM in the context of VenG, BM assessments may not be required for these patients. Disclosures Fischer: Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Al-Sawaf:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Tandon:Roche: Equity Ownership; Roche Products Ltd: Employment. Fink:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: travel grants. Stübig:Hexal: Speakers Bureau. Brüggemann:Amgen, Celgene, Janssen: Honoraria, Speakers Bureau; Amgen, Janssen: Membership on an entity's Board of Directors or advisory committees; affimed, Amgen, Celgene, Regeneron: Research Funding; Amgen, Incyte, PRMA: Consultancy. Jiang:Genentech: Employment, Equity Ownership; F. Hoffman-La Roche: Equity Ownership. Schary:Abbvie: Employment, Equity Ownership. Eichhorst:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees. Wendtner:MorphoSys: Consultancy, Honoraria, Research Funding; GILEAD Science: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-CILAG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Kreuzer:Roche and Abbvie: Honoraria, Other: Expert testimony. Langerak:F. Hoffmann-La Roche Ltd: Research Funding; Gilead: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Genentech, Inc.: Research Funding. Goede:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, Speakers Bureau; janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau. Böttcher:AbbVie: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding; Janssen-CILAG: Honoraria, Other: Travel grants, Research Funding; Roche: Honoraria, Research Funding; Genentech: Research Funding; Becton Dickinson: Research Funding; Novartis: Research Funding. Stilgenbauer:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau.

Abstract: Introduction CLL11 is a large randomized phase 3 trial investigating first-line chemoimmunotherapy in CLL patients with comorbidities, i.e. patients typically treated in daily practice. Here, we present: (i) The final stage 2 analysis with efficacy and safety results of the head-to-head comparison between GA101 plus Clb (GClb) and rituximab plus Clb (RClb); at the pre-planned interim analysis, the primary endpoint was met early and the results were released by the independent data monitoring board. (ii) An update on the stage I analysis (GClb vs. Clb and RClb vs. Clb comparisons) with longer observation time; the final stage 1 analysis recently showed that GClb or RClb has superior efficacy to chemotherapy with Clb alone. Methods Treatment-naïve CLL patients with a Cumulative Illness Rating Scale (CIRS) total score 〉 6 and/or an estimated creatinine clearance (CrCl) 〈 70 mL/min were eligible. Patients received Clb alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), GClb (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or RClb (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Primary endpoint was investigator-assessed progression-free survival (PFS). Response rates, minimal residual disease (MRD), and overall survival (OS) were key secondary efficacy endpoints. Results Final results of the stage 2 analysis: Median observation time was 19 months. The GClb and RClb treatment arms were well balanced for baseline characteristics. Median age, CIRS score, and CrCl at baseline were 73 years, 8, and 63 mL/min respectively. Key efficacy and safety results are shown in the table. The PFS benefit of GClb over RClb was supported by all pre-planned subgroup analyses (including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-). The number of patients with MRD negative blood samples at end-of-treatment was more than 10-fold higher with GClb compared with RClb (63/214 [29.4%] vs. 6/243 [2.5%] ). Grade 3-4 infusion-related reactions with GClb occurred at first infusion only. Updated results of the stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 results, GClb or RClb compared with Clb alone was associated with statistically significant and clinically meaningful improvement in PFS (GClb vs. Clb: HR 0.18, CI 0.13-0.24, p 〈 .0001, RClb vs. Clb: HR 0.44, CI 0.34-0.57, p 〈 .0001). The updated median PFS in GClb, RClb and Clb were 26.7, 16.3 and 11.1 months, respectively. Updated OS analysis demonstrated a benefit of GClb over Clb (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for RClb over Clb showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the GClb, RClb, and Clb arms, respectively, had died. OS medians were not reached. Conclusions GA101, a novel, glycoengineered, type II CD20 antibody, in combination with Clb (GClb regimen) demonstrated statistically significant and clinically meaningful prolongation of PFS, and higher complete response rate and MRD negativity rate compared with RClb in previously untreated CLL patients with comorbidities. Infusion-related reactions and neutropenia were more common with GClb without an increase in infections. Furthermore, GClb vs. Clb alone demonstrated a prolongation of OS. Overall, GClb is superior to RClb and a highly active treatment in this typical CLL patient population. Disclosures: Goede: Mundipharma: Honoraria; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Fischer:Mundipharma: Travel grants, Travel grants Other; F. Hoffmann-La Roche: Travel grants Other. Engelke:F. Hoffmann-La Roche: Travel grants Other. Eichhorst:Mundipharma: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy; F. Hoffman-La Roche: Honoraria, Research Funding. Wendtner:F. Hoffmann-La Roche: Consultancy, Research Funding. Dilhuydy:F. Hoffmann-La Roche: Consultancy. Opat:F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Owen:F. Hoffmann-La Roche: Honoraria. Kreuzer:F. Hoffmann-La Roche: Consultancy, Honoraria. Langerak:F. Hoffmann-La Roche: Research Funding. Ritgen:F. Hoffmann-La Roche: Research Funding. Stilgenbauer:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Asikanius:F. Hoffmann-La Roche: Employment. Humphrey:F. Hoffmann-La Roche: Employment. Wenger:F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

Abstract: Abstract 333 Background: Standard chemotherapy for elderly AML patients results in a median overall survival of only about one year. Case reports and early phase I/II data have shown that the kinase inhibitor Sorafenib might show clinical benefit for Flt3-ITD-positive AML patients (Metzelder S Blood 2009; 113:6567) and that its addition to standard chemotherapy is feasible (Ravandi F JCO 2010; 28:1856). Sorafenib is a potent Raf, c-Kit and FLT3 inhibitor that may also affect AML blasts and bone marrow (BM) stroma cells via VEGFR and PDGFR-β inhibition. Therefore, we performed a multicenter, randomized, placebo-controlled, double-blind phase II trial in elderly ( & gt;60 y) AML patients analyzing the effect of Sorafenib in addition to standard chemotherapy and as a maintenance therapy for up to one year. Methods: 197 AML patients in 16 centers received up to two cycles of standard 7+3 induction chemotherapy plus two cycles of consolidation therapy with intermediate dose (6 × 1g/sqm) AraC. Before start of treatment, they were randomly assigned to receive either placebo or Sorafenib (400 mg bid between the cycles and after chemotherapy for up to one year after start of induction). The primary aim was to compare the event-free survival (EFS) of the two treatment groups. Secondary end points were to compare EFS and overall survival (OS) of predefined subgroups according to NPM and FLT3 mutation status and toxicity of treatment. Results: Among the 197 evaluable patients, 102 pts received Sorafenib and 95 pts placebo. EFS and OS were not significantly different between the two treatment groups (placebo vs. Sorafenib: EFS: Median: 7 vs. 5 months, hazard Ratio (HR): 1.261(p=0.13); OS: Median: 15 vs. 13 months, HR 1.025 (p=0.89)). CR or blast clearance without complete blood count recovery was observed in 49 (48%) and 9 (8.8%) Sorafenib patients and 57 (60%) and 4 (4.2%) placebo pts, respectively. Exploratory subgroup analyses did not reveal any significant difference between the treatment groups but showed a tendency towards decreased EFS in the Sorafenib arm for NPM1-wild type AML cases. Flt3-ITD mutations were found in 28 out of 197 patients (14.2%), in line with the reported incidence in the target population. No differences in EFS or OS were to be noted in this small patient population. Also, CR rate was not improved by the study drug in this subgroup of patients. Sorafenib was relatively well tolerated. The most frequent adverse events (AE) ≥grade 3 were febrile neutropenia, pneumonia in neutropenia, sepsis, diarrhea, skin rash, mucositis, hypertension (77 vs 74, 54 vs 35, 15 vs 15, 17 vs 6, 14 vs 7, 9 vs 6, 8 vs 5 events in the Sorafenib vs the placebo group). A hand-foot-skin reaction (≥grade 3) was noted in 5 vs 0 events in Sorafenib vs control pts. There was a trend of slower regeneration of leukocytes and thrombocytes within the Sorafenib arm compared to the control arm after the first and second induction course but not after consolidation cycles. Conclusion: Although the combination regimen appeared to be feasible and tolerable in elderly AML pts, Sorafenib treatment did not improve EFS or OS in this unselected elderly AML patient population. Further studies should focus on selected AML target populations for Sorafenib, especially FLT3-ITD+ AML patients. Disclosures: Off Label Use: Sorafenib (multikinase inhibitor) is given in combination with standard chemotherapy in elderly AML patients. (See title of the abstract!).

Abstract: Background: Patients (pts) withHR-MDS have a median OS of 4 to 6 months (mo) after HMA failure (Prebet et al, J Clin Oncol 2011) and no approved salvage therapy. Development of new therapeutics for this population will benefit from the availability of surrogate endpoints and markers that can predict survival. Gore et al established response to azacitidine (Vidaza®) in first-line therapy for HR-MDS as a reasonable surrogate to predict survival (Gore et al, Haematologica 2013). Rigosertib, a novel dual PI3K/PLK pathway inhibitor, has been shown to reduce bone marrow blasts (BMBL) in these pts (Seetharam et al, Leuk Res 2012). Silverman et al described complete or partial bone marrow (BM) response, or stabilization after 4-8 weeks (wks) of treatment with rigosertib as a potential surrogate for predicting survival in pts with HR-MDS after failure of primary HMA therapy (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized Phase III trial. Methods:Pts with HR-MDS were randomly assigned 2:1 to rigosertib or best supportive care (BSC) after progressing on, failing to respond to, or relapsing after HMA treatment. BM aspirates were assessed pretreatment, at 4 weeks and at 8-week intervals thereafter. Central slide review was undertaken in a representative population of samples. The BMBL response at each time point was assessed using the following definitions: bone marrow complete response (mCR) = BMBL ≤ 5% and decrease of ≥ 50% from baseline; bone marrow partial response (mPR) = BMBL decrease from baseline of ≥ 50%, but BMBL still 〉 5%; stable disease (SD) = BMBL decrease or increase from baseline of 〈 50%; progressive disease (PD) = BMBL increase from baseline of ≥ 50% by an absolute minimum of 5%; Not evaluable (NE). Results:Bone marrow assessment was carried out in 156 patients (pts) on the rigosertib arm and 24 pts on the BSC arm at 4 wks after enrollment, and in 86 and 20 pts, respectively, at 12 wks. The invasive BM procedure was optional on the BSC arm, which accounts for the low number of assessments in this group. BM responses at the 2 time points are presented in Table 1. Since no difference in overall survival was noted between pts who had objective BM response and those who did not progress (ie, stable disease), a landmark analysis was conducted that separated pts who were alive at the 4-wk landmark time into two 4-wk response categories: BM response + SD vs. PD. Results of this analysis in rigosertib-treated patients were statistically significant at p = 0.011, with a hazard ratio (HR) of 0.62 and a median OS (from 4 wks onward) of 9.8 months in the mCR + mPR + SD group vs. 4.6 months in the PD group (Figure 1). Another landmark analysis was conducted at 12-wks. Results of this analysis were also significant (p 〈 0.001) in rigosertib-treated patients, with an HR of 0.39 and a median OS (from 12 wks onward) of 10.4 months in the mCR + mPR + SD group vs.7.5 months in the PD group (Figure 2). A time-dependent Cox regression of OS by 4-wk BMBL response reinforced the validity of the 4-wk and 12-wk BM assessments as surrogate biomarkers for survival (Table 2). Conclusions: These data suggest that BMBL response at 4 or 12 weeks was correlated with OS in this population of pts with HR-MDS treated with rigosertib after HMA failure and are consistent with previous observations in Phase II studies. Table 1 4- and 12-week Bone Marrow Blast Response (Intention-to-Treat Population) Number (%) of Patients 4-wk BMBL Response 12-wk BMBL Response Rigosertib N = 199 BSC N = 100 Rigosertib N = 199 BSC N = 100 Pts with BMBL assessment 156 (78) 24 (24)* 86 (43) 20 (20)* BM complete response (mCR) 22 4 11 5 BM partial response (mPR) 8 2 9 2 Stable disease (SD) 77 9 32 8 Progressive disease (PD) 49 9 34 5 * Bone marrow assessment was not required on the BSC arm. Figure 1 Figure 1. Figure 2 Figure 2. Table 2 Time-dependent Cox Regression of Overall Survival by Bone Marrow Blast Response Analysis Rigosertib BSC Wald P-value Hazard Ratio (95% Confidence Interval) Wald P-value Hazard Ratio (95% Confidence Interval) By 4-wk BMBL response 0.051 0.72 (0.51 - 1.00) 0.56 0.83 (0.45 - 1.54) By 12-wk BMBL response 0.0005 0.55 (0.39 - 0.77) 0.16 0.68 (0.39 - 1.17) *Stratified by pretreatment BMBL: 5%-19% vs. 20%-30% Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Azarnia:Onconova Therapeutics, Inc: Employment.

Abstract: Abstract 1787 Recent studies have described an extensive expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1) on the surface of malignant B cells in patients suffering from chronic lymphoid leukemia (CLL). ROR1 expression has also been detected in ovarian cancer, renal cancer, melanoma, and lung adenocarcinoma, suggesting a general role of ROR1 in cancer genesis and/or maintenance. However, low levels of ROR1 mRNA or protein expression have also been found on undifferentiated embryonic stem cells, adipose tissue and on early stage of B-cells in bone marrow, but not in major adult tissues and peripheral B cells. In contrast, our results describe for the fist time expression of ROR1 on rare B cells in peripheral blood of healthy donors. Using magnetic cell sorting techniques we were able to enrich ROR1 positive B cells from PBMCs of healthy donors. The average frequency of ROR-1+ B cells in PBMCs ranged from 1×10−3 to 1×10−4. Interestingly, ROR1+ B cells revealed a heterogeneous phenotype and could further be classified into a CD19+/CD27+/CD38− and a CD19+/CD27−/CD38+ subpopulation as assessed by flow cytometry. Remarkably, in contrast to the CD27+ subpopulation the CD38+ subpopulation showed higher levels of CD5 and CD23 expression, which are both markers known to be upregulated on B cells of CLL patients. Both populations do not show elevated expression of transcription factor ZAP70 and Bcl-2 but expressed higher level of Bcl-6 compared to CD19 B cells. Bcl-6 is known to be required for pre-B cell self-renewal but has also been described to play an essential role in resistance of leukemic cells to therapeutic tyrosine kinase inhibitors. Moreover ROR1+ B cells revealed an immature and non-activated sate as evidenced by the expression of IgD and IgM, and the lack of IgG and CD69. Further functional examination and immunophenotyping of these rare cells are under investigation. We have identified rare B cells expressing the tumor-associated receptor tyrosine kinase ROR1, which are heterogenic in CD27 and CD38 expression and show an immature phenotype. We are currently assessing a potential relationsphip ROR1+ peripheral B cells and ROR1 expressing B cells in malignancies like CLL, mantel cell (MCL) and marginal zone lymphoma (MZL). Disclosures: Milleck: Miltenyi Biotec GmbH: Employment. Assenmacher:Miltenyi Biotec GmbH: Employment. Schmitz:Miltenyi Biotec GmbH: Employment. Jähn:Miltenyi Biotec GmbH: Employment.

Abstract: Introduction FCR is the current standard first line treatment regimen in advanced CLL (Hallek et al., Lancet, 2010), but is associated with significant side effects. The GCCLSG initiated an international phase III study in order to test the non-inferiority regarding efficacy and potentially better tolerability of BR compared to FCR in first-line therapy of physically fit pts without del(17p). Methods and Patients 688 CLL pts from 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) were screened centrally for immunophenotype, genomic aberrations by FISH, IGHV sequenzing, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between October 2008 and June 2011. Pts were randomly assigned to receive 6 courses of either FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days) or BR (N=280; B 90mg/m2 i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days). The intent-to-treat population consisted of 561 pts, because three patients were excluded due to deferred treatment (1 pt decision, 1 treatment before randomization, 1 misdiagnosis). 22 % were Binet A, 38 % Binet B and 40 % Binet C. The median age was 62 years (yrs) (range 33 to 82), median CIRS score 2 (range 0-6). There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%; p=0.003). All other characteristics including median age were well balanced. A mean number of 5.27 courses was given in the FCR arm versus 5.41 courses in the BR arm (p=0.022). 70.6% (FCR) and 80.3% (BR) of pts received 6 courses (p=0.008). Dose was reduced by more than 10% in 27.3% (FCR) and 31.6% (BR) of all courses given (p = 0.012). Results The median observation time was 27.9 months (mo) in all pts alive. While response evaluation was missing in 14 pts, 547 pts (274 FCR; BR 273) were evaluable for response and all 561 pts (282 FCR; 279 BR) for progression-free survival (PFS), event-free survival (EFS) and OS. The overall response rate was identical in both arms with 97.8% (p=1.0). The complete response rate (CRR) (confirmed by central immunhistology) with FCR was 47.4% as compared to 38.1% with BR (p=0.031). MRD data were available at interim analysis from 192 pts (99 FCR; 93 BR) of the first 300pts. 71.7% of pts in the FCR and 66.7% in the BR arms achieved MRD-levels below 10-4 in peripheral blood at final staging (p=0.448). The complete MRD data set will be available by November. PFS was 85.0% at 2 yrs in the FCR arm and 78.2% in the BR arm (p=0.041). EFS was 82.6% at 2 yrs in the FCR arm and 75.7% in the BR arm (p=0.037).There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593). Hazard Ratio for PFS, EFS and OS was 1.385, 1.375 and 0.842 respectively. PFS was assessed in pts 〈 65 yrs and ≥ 65 yrs. While there was a significant difference in pts 〈 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757). A multivariate analysis including treatment arm, Binet stage, age, sex, comorbidity, serum TK, serum beta2-microglobulin (Beta2M), del(11q) and IGHV status identified treatment arm, Beta2M, del(11q) and IGHV as independent prognostic factors for PFS and EFS. FCR treated pts had significantly more frequent severe, CTC grade 3 to 5, adverse events during the whole observation period (90.8% vs 78.5%; p 〈 0.001). Especially severe hematotoxicity was more frequent in the FCR arm (90.0% vs 66.9%, p 〈 0.001). The higher rate of severe neutropenia (81.7% vs 56.8%, p 〈 0.001) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%, p=0.001) in the FCR arm, especially in the elderly (FCR: 47.4% vs BR: 26.5%; p=0.002). Treatment related mortality occurred in 3.9% (n=11) in the FCR and 2.1% (n=6) in the BR arm. Conclusion The results of this planned interim analysis show that FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections, associated with FCR. In light of these results, no firm recommendation of one regimen over the other can be given at the present time regarding the first-line use in CLL pts with good physical fitness. Disclosures: Eichhorst: Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Gregor:Roche: Consultancy, Honoraria, Travel Support Other; Mundipharma: Travel Support, Travel Support Other. Plesner:Mundipharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Kneba:Roche: Consultancy, Research Funding. Wendtner:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Böttcher:Roche: Honoraria, Research Funding. Hallek:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding.

Abstract: Introduction: In chronic lymphocytic leukemia (CLL), improved anti-CD20 antibodies such as obinutuzumab (GA101) and targeted drugs, such as ibrutinib, show very good efficacy and tolerability. With the CLL2-BIG trial, the German CLL Study Group designed a regimen composed of obinutuzumab and ibrutinib for induction and maintenance therapy. Patients with high tumor burden receive bendamustine as debulking resulting in the proposed "sequential triple-T" concept [Hallek M., Blood 2013] of a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD). Here we present the results of the primary endpoint analysis of the trial. Methods : This prospective, open-label, multicenter phase-II trial investigates the efficacy and safety of a novel regimen for physically fit and unfit CLL patients (pts) requiring treatment, irrespective of high-risk genetics. 62 pts were to be recruited according to a predefined allocation for the two strata of first-line and relapse/refractory treatment. Six cycles of induction treatment with obinutuzumab and ibrutinib were administered followed by maintenance therapy with continuous ibrutinib and obinutuzumab every three months until achievement of an MRD-negative complete remission or up to 24 months. Pts with an absolute lymphocyte count ≥ 25.000/µl and/or lymph nodes ≥ 5cm received two cycles of bendamustine before start of induction. The primary endpoint is overall response rate (ORR) three month after the start of last induction cycle administered; secondary endpoints include ORR after debulking, MRD evaluations and safety parameters (graded per the NCI CTCAE v.4 criteria). Results: 66 pts were enrolled between January and August 2015. Five pts completed less than two cycles of induction and were therefore excluded from the full analysis set as defined by protocol. The current analysis includes 58 pts; an update including all 61 pts will be available for presentation at the meeting. The median age was 65.5 (range 36-83) years and the median time since initial diagnosis was 56.2 (2.1 - 222.8) months. 27 pts were treatment-naïve and 31 relapsed/refractory with a median of one prior treatment line (1-5). Baseline characteristics are summarized in table 1. 41 pts (71%) received bendamustine debulking, of these 27 pts (66%) responded; five pts (12%) achieved clinical complete remission (CR), 3 pts (7%) clinical CR with incomplete recovery of the bone marrow (CRi) and 19 pts (46%) partial remission (PR). 57 pts completed six cycles of induction treatment. One patient died after the fifth course due to grade 5 duodenitis related to study therapy. The combination showed promising efficacy with an ORR of 100% by investigator assessment at the end of induction. Statistically, the primary endpoint was met and the null hypothesis could be rejected. Response rates are presented in table 2. 27 pts (47%) achieved MRD negativity ( 〈 10-4 by flow cytometry) in peripheral blood (pB) at the end of induction. An intermediate MRD-status (≥ 10-4 and 〈 10-2) was found in 15 pts (26%) whereas 13 pts (22%) were MRD positive (≥ 10-2). In three pts (5%) no MRD sample was available. So far, 38 pts (65%) received at least one dose of maintenance treatment; one patient already stopped treatment due to MRD negativity as defined per protocol. CTC Grade 3-4 adverse events occurred in 19 pts (33%) during induction therapy. The most common toxicities observed are shown in table 3. *The table includes all grade 3-4 AEs regardless of frequency and AEs of any grade observed in at least six patients. Conclusion: With an ORR of 100% and an MRD negativity rate of 47% in the pB the BIG-regimen showed a very good efficacy in a heterogeneous study population. No major toxicity occurred so far. Table 1. Demographics and baseline characteristics Table 1. Demographics and baseline characteristics Table 2. Response rates Table 2. Response rates Table 3 Safety Table 3. Safety Disclosures von Tresckow: Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; Celgene: Other: Travel grants; Hoffmann-LaRoche: Other: Travel grants, Research Funding. Cramer:Astellas: Other: Travel grants; Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; GlaxoSmithKline/Novartis: Research Funding; Gilead: Other: Travel grants, Research Funding; Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Mundipharma: Other: Travel grants. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Engelke:Hoffmann-LaRoche: Other: Travel grants. Langerbeins:Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; Mundipharma: Honoraria, Other: Travel grants, Research Funding. Fink:Mundipharma: Other: Travel grants; Celgene: Other: Travel grants, Research Funding; AbbVie: Other: Travel grants; Hoffmann-LaRoche: Other: Travel grants. Illmer:Hoffmann-LaRoche: Honoraria, Other: travel grants. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fischer:Hoffmann-LaRoche: Other: Travel grants. Wendtner:Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding. Böttcher:AbbVie: Honoraria, Research Funding; Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding. Eichhorst:Abbvie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Hallek:Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Abstract: In acute myeloid leukemia (AML) the subset with complex karyotype (CK) is traditionally regarded as the worst prognostic group. However, ≥ 3, ≥ 4, or ≥ 5 abnormalities have been variably used for its definition. Recently, monosomal karyotype (MSK) was suggested to indicate an even inferior outcome. We tested which definition fits best to identify the most unfavorable subgroup. After excluding patients with t(15;17)/PML-RARA, t(8;21)/RUNX1-RUNX1T1, inv (16)/t(16;16)/CBFB-MYH11, and normal karyotype, 824 patients with AML with cytogenetic abnormalities were analyzed. Patients with MSK or CK defined as ≥ 3, ≥ 4, or ≥ 5 abnormalities showed an inferior overall survival compared with the respective remaining patients not fulfilling these criteria (for all, P 〈 .001). Hazard ratios were 1.93, 1.68, 1.94, and 1.92. CK ≥ 4 as a single parameter identified the largest proportion of patients with very poor risk. However, combining CK ≥ 4 and MSK detected an even larger number of patients with very unfavorable outcome (261 of 824; 31.7%).

Abstract: Abstract 1587 Poster Board I-613 In chronic lymphocytic leukemia (CLL) WNT signaling is constitutively active and several members of this signaling pathway are uniformely upregulated in these cells. Apart from classical WNT receptors like FZD and LRP6, receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been shown to function as a receptor for WNT proteins, too. Furthermore, it could recently be demonstrated that ROR1 is frequently expressed on the surface of CLL cells and might therefore serve as a therapeutic target in this disease. However, so far only little is known about the expression status of this protein in different patients. Moreover, a diagnostic antibody for flow cytometric investigations is lacking. Thus, the aim of our study was to i) establish a directly labelled anti-ROR1 antibody for flow cytometry, ii) to confirm previous results on ROR1 expression in CLL, iii) to investigate ROR1 expression in different cell compartments and iv) correlate our findings to known markers of risk and disease progression. Peripheral blood of CLL patients as well as healthy volunteers was subjected to flow cytometric analysis. Besides standard determination of leukocyte subpopulations ZAP70 and CD38 status was assessed according to current diagnostic recommendations. In addition, ROR1 surface expression was first detected by flow cytometry using a specific primary antibody directed against ROR1 and a fluorescent labelled secondary antibody. Using this experimental setting we found that ROR1 is expressed on 63.4% of all neoplastic CLL cells and also on 30.5% of T cells in the peripheral CLL blood. In contrast, no ROR1 expression could be detected on NK cells, B cells, CD8+- or CD4+-T cells of healthy individuals. To improve the analytical technique the ROR1 antibody was directly conjugated with Phycoerythrin (PE) and the experiments were repeated. With the conjugated antibody we detected ROR1 expression on 97.1% of neoplastic CLL cells and virtually on no T lymphocytes. ROR1 expression levels correlated neither with the expression of ZAP70 nor with CD38. Again, we could not detect ROR1 expression on peripheral blood cells of our healthy volunteers. Taken together, ROR1 expression appears to be highly restricted to CLL cells. If in addition to CD5 and CD19 ROR1 detection is included into diagnostic flow cytometric panels the specificity and sensitivity of immunophenotypic CLL diagnostics may be greatly enhanced. Disclosures Hallek: Roche: Consultancy, Honoraria, Research Funding.

Abstract: Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.