Abstract: Recently we demonstrated that RIC with busulfan, fludarabine and ATG followed by allogeneic hematopoietic stem cell transplantation (HSCT) induced molecular remissions in patients (pts) with advanced CLL. However, this approach was hampered by severe GVHD. In an attempt to lower the rate of severe GVHD we replaced ATG by campath in a new study protocol. Patients and Methods: 20 pts with a median age of 54 years (range, 43 to 64) and advanced CLL were included. A median of 3 prior chemotherapy regimens had been given before HSCT, including fludarabine-containing regimens in all but two pts with autoimmune hemolysis. High risk cytogenetic features (17p−, 11q−, +12) were present in 9 pts. After conditioning with busulfan (8 mg/kg), fludarabine (150 mg/m2) and campath (75 mg) on days −9 to −5 peripheral blood stem cells from matched related (n=4) or unrelated donors (n=16) were transplanted. GVHD prophylaxis consisted of CSA monotherapy. Campath levels were analysed in frozen serum samples by BioAnaLab, Oxford, UK. Results: Two pts had no detectable campath level at the day of HSCT, while four pts had levels between 0.5 to 1.8 microgram/mL. Regeneration of neutrophils ( 〉 0.5/nl) and platelets ( 〉 20/nl) required a median of 17 (range, 14–25) and 10 (range, 0–27) days, respectively. Incomplete T-cell chimerism ( 〈 50%) was observed in 7 pts and subsequently 3 pts experienced secondary graft failure on days 134, 152 and 324. Six pts received donor lymphocyte infusions (DLI) for the conversion of incomplete T-cell chimerism (N=4) or progressive disease (N=2). Sponaneous acute GVHD II° to IV° occurred in 9/20 pts. After DLI four additional pts developed acute GVHD II° to IV°. Limited chronic GVHD occurred in 9 and extensive disease in 2 pts. In CMV seropositive pts the day 100 probability of CMV infection was 74% (95% CI, 44% to 100%). Severe encephalitis (HHV6, EBV and JC virus as suspected agents) was observed in 5 pts. Two pts recovered without sequelae, 2 pts are cognitively handicaped and one pt died. Hemorrhagic cystitis (CTC 2/3) occurred in 2 pts. After a median follow-up of 13 months (range, 6 – 26 months), 15 pts are alive. Four pts died from treatment related complications. Causes of death were pneumonia of unknown etiology (N=2), encephalitis (N=1) and GVHD grade IV (N=1). One pt died from severe acute GVHD subsequent to the treatment of relapse with DLI. One-year overall and progression-free survival was 75% (95% CI, 55% to 95%) and 50% (95% CI, 25% to 75%), respectively. The one-year probability of non-relapse mortality was 20% (95% CI, 2% to 38%). The number of binding sites for campath is highly variable in pts with progressive CLL resulting in interindividually highly variable pharmacokinetics. Differences in the extent of in vivo T-cell depletion might therefore explain the individually varying T-cell engraftment pattern. In addition, the high incidence of severe viral infections reflects impaired immunoreconstitution. Including pts after DLI we observed a substantial rate of severe GVHD. Based on these data we decided to skip the strategy of in vivo T-cell depletion with campath in patients with CLL.

Abstract: Introduction: The CD19 antigen is an attractive therapeutic target as it is highly expressed in chronic lymphocytic leukemia (CLL). CD19 is not down-regulated in patients (pts) pretreated with CD20-targeting agents and has a signaling function that promotes the malignant phenotype. In preclinical studies, the Fc-enhanced, humanized, CD19 antibody MOR208 showed synergistic potential in combination with venetoclax (VEN, a small molecule selective inhibitor of the apoptosis regulator BCL-2). Pts with relapsed or refractory (R/R) CLL who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have poor prognosis. A previous phase I study showed that MOR208 was well tolerated, with encouraging single-agent activity in pts with R/R CLL. This ongoing phase II study was designed to assess the safety and preliminary efficacy of MOR208 in combination with idelalisib (Cohort A) or VEN (Cohort B) in pts with R/R CLL previously treated with a BTKi. Results of Cohort A were previously published at EHA 2018 (Poster PF350). Here we report the initial safety and efficacy results for Cohort B. Methods: Adult pts with R/R CLL without transformation or Richter's syndrome, who progressed on BTKi therapy or were intolerant to a BTKi during their last prior therapy, were eligible if they had ECOG performance status 0-2 and adequate organ function. In Cohort B, pts were treated until progression or for up to 24 cycles (C; 28 days (D)/C). MOR208 was administered intravenously at 12 mg/kg body weight, starting from C1D1, weekly during C1-3 (with an equivalent loading dose on D4 of C1), every other week in C4-6, and monthly in C7-24. Oral VEN was administered daily starting from C1D8 on a weekly ramp up dosing schedule, starting at 20 mg on C1D8, increasing to 50 mg on C1D15, 100 mg C1D22, 200 mg C2D1 and reaching the full daily dose of 400 mg from C2D8 onwards. Primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to IWCLL 2008 guidelines. Results: We report preliminary results of Cohort B with a data cutoff date of June 18, 2018 and a median observation time of 4.6 months. Recruitment in Cohort B was completed with 13 pts who received at least one dose of MOR208. Eleven pts started combination treatment with VEN; 10 pts completed at least 5 weeks of combination treatment, reaching the full daily dose of VEN. Baseline characteristics are shown in Table 1. All pts had received ibrutinib therapy and 1 pt had subsequent acalabrutinib treatment. The median number of prior treatment lines, including BTKi therapy in all 13 pts, was 3 (range 1-4). Table 2 summarizes treatment-emergent (TE)AEs. The most common hematological TEAE was neutropenia (38%). Eleven TE serious (S)AEs were reported in 9 pts (69%); all resolved. One grade 3 SAE, tumor lysis syndrome, occurred at ramp up to 50 mg VEN. The pt recovered after treatment and continued VEN 50 mg the day after event onset. Three serious adverse reactions (2 pts with infusion-related reactions, 1 pt with bone pain with pyrexia) were reported in total. Two pts (15%) permanently discontinued study treatment due to an infusion-related reaction arising during MOR208 monotherapy (i.e. before C1D8). One pt (8%) discontinued study participation due to withdrawal of informed consent, when on a dose of 50 mg VEN. The 3 discontinued pts did not undergo a response assessment. Treatment of 10 pts is ongoing and seven pts had at least 1 post-baseline assessment of tumor response on C4D1; all (7/7) had a partial response (PR) based on local investigator assessment. Conclusions: The novel combination treatment of MOR208 with VEN showed generally acceptable safety and tolerability as well as encouraging antitumor activity in pts with R/R CLL who discontinued prior treatment with a BTK inhibitor. Disclosures Staber: Janssen: 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; Celgene: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munir:Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Schetelig:Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Middeke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Weirather:MorphoSys: Employment. Parikh:MorphoSys: Research Funding; Gilead: Honoraria; Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding. Stilgenbauer:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding.

Abstract: CLL with deletion 17p (17p-) or refractory to fludarabine (F)-based regimens is characterized by poor prognosis. The cooperative French/German CLL2O study aimed at achieving deep and durable response in this population by combining alemtuzumab (A) and dexamethasone (D) induction, followed by consolidation with A maintenance or allogeneic stem-cell transplantation (allo-SCT). Induction treatment consisted of subcutaneous A (30mg, 3x weekly) combined with oral D (40 mg days 1-4 and 15-18), both at 28 day cycles, and prophylactic pegfilgrastim 6 mg on days 1 and 15. If at least SD was achieved after 3 cycles, consolidation was scheduled with either allo-SCT or A maintenance (30mg every 2 weeks for up to 2 years), at discretion of pt and physician. Between January 2008 and December 2011, 131 eligible pts were enrolled at 26 centers. Pts were generally subdivided for this analysis into three cohorts: 17p- 1st line, 17p- relapsed (not refractory) and refractory (i.e. no response or relapse within 6 months) to F-based or similar (i.e. pentostatin, cladribine, bendamustine) therapy. All three cohorts where characterized by high-risk baseline disease features (detailed in Table). During induction, a total of 467 non-hematologic AEs were recorded, predominantly (79%) of minor grade, while 36%, 43%, and 50% of pts in the 3 cohorts had at least one event of grade 3 or higher (Table). ORR (best response) was high in all three cohorts, but CRs were rarely observed outside the 17p- 1st line cohort (Table). Correspondingly, there were marked differences in PFS and OS between the three cohorts with far better outcome in the 17p- 1st line group (see Table and Figure 1). Consolidation treatment was performed as A maintenance (median duration 42 weeks, range 2 – 112.4) in 37%, and allo-SCT in 25%, with a median age of 69 and 57 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection in 19 patients (15%), largely from the F-refractory cohort (n=16), with the majority being non-responders to study treatment (n=11); CLL progression (10%), and other toxicity (9%). Five pts who did not receive immediate consolidation treatment per protocol later underwent allo-SCT, 2 of these have died (sepsis, GvHD). During A maintenance, grade 3/4 toxicity consisted of neutropenia in 47% and thrombocytopenia in 12%. Serious (grade 3/4) non-CMV infection occurred in 17%, 10%, 13% in the 3 cohorts. When comparing PFS between A maintenance and allo-SCT, there were 41 (84%) and 16 (48%) events, respectively, significantly favoring SCT (Figure 2). Six pts who started A maintenance later underwent allo-SCT, 4 of them after relapse. After median follow up of 20 months from allo-SCT, 12 pts have died, 7 because of non-relapse mortality and 5 subsequent to CLL progression. In conclusion, the combination of A and D, followed by A maintenance or allo-SCT showed high response rates in ultra high-risk CLL with expected toxicity. For 17p- 1st line treatment, the results compare favorably to FCR (CLL8: ORR 68%, median PFS 11.3 mo). On the other hand, in F-refractory and 17p- relapsed CLL, the high ORR did not translate into prolongation of PFS. Allo-SCT appears to offer superior disease control in eligible patients despite prior A exposure. Overall, this mature trial may serve as a historical benchmark for comparison of novel agents in ultra high-risk CLL. Table 1 Parameter 17p- 1st line 17p- relapsed F-refractory Number of patients 42 28 61 Median age (yrs) 66.5 64 66 Binet C (%) 45 57 77 B symptoms (%) 40 32 31 ECOG 1/2 (%) 38 39 56 Median thymidine kinase (U/l) 35 48.1 27.6 Median β2MG (mg/dl) 3.8 5.1 4.7 Unmutated IGHV (%) 90 93 87 17p- (%) 100 100 49 Prior lines (median) n.a. 2 3 Prior rituximab (%) n.a. 71 93 AEs during induction (grade 3/4) Table 2 All AEs (%) 36 43 50 Neutropenia (%) 24 36 67 Anemia (%) 14 36 21 Thrombocytopenia (%) 12 39 31 Non-CMV infection (%) 19 36 36 CMV infection (%) 7 0 2 Efficacy (median follow-up 41.3 mo) Table 3 ORR (%) 97 79 69 CR (%) 21 4 3 Median PFS (mo) 32.8 10.3 9.7 Median OS (mo) 〉 60.0 21.4 17.3 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Stilgenbauer: Amgen: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

Abstract: Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and & gt;15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; & gt;95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and & gt;15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, & gt;15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and & gt;60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract: Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib ( n  = 134) or placebo ( n  = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p  = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p  = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p  = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

Abstract: Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10 −4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD 〈 10 −4 was achieved in this high-risk population.

Abstract: Background: Most patients (pts) diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy in medically fit pts is still the standard practice and a prerequisite for long-term survival, elderly pts have a higher risk of treatment related morbidity and lower remission rates than younger AML pts. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML pts (Niederwieser et al., Blood 2002, abstr. 1337). We present the mature final results of a randomized-controlled trial comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA). Patients and Methods: In the 60+ trial of the Study Alliance Leukemia (SAL), AML pts 〉 60 years and medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). All pts in CR after DA received intermediate-dose cytarabine plus amsacrine (MAMAC) as consolidation treatment, whereas pts in CR after IMA were consolidated with standard-dose cytarabine plus mitoxantrone (2+5). Primary study endpoint was the CR rate with an expected difference of 15% in favor of IMA. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: Between February 2005 and October 2009, 852 pts were screened for study inclusion and 485 pts started study treatment, of which 241 pts were randomized for treatment arm A (DA) and 244 for treatment arm B (IMA). The median age was 69 years. Pt characteristics were equally distributed between the two arms. According to a strict definition, all patients with early death, study drop-out, or failed remission assessment were categorized as being not in CR. The CR rate amongst all 485 pts treated in the study was 47%. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). If all first CRs were taken into account including those achieved after trial discontinuation, the CR rates after DA versus IMA induction were 55% versus 64% (p=0.043). Separate analyses addressing age, cytogenetics, de novo AML, NPM1 and FLT3-ITD confirmed higher CR rates after IMA induction throughout these subgroups. Six-week mortality was 14% in both arms. The median duration of ≥ grade 3 neutropenia was 23 days after DA I and 25 days after IMA (p=0.031). The median duration of thrombocytopenia ≥ grade 3 was 16 versus 20 days after DA I and IMA I, respectively (p 〈 0.001). The incidences of non-hematologic toxicities were not significantly different except for a higher incidence of liver toxicity (odds ratio IMA/DA = 0.52; p=0.001) and gastrointestinal symptoms (OR IMA/DA = 0.62; p=0.041) after DA. In the course of treatment, 11 pts in each arm (5%) received allogeneic stem cell transplantation. After a median follow-up of 66 months, RFS curves are superimposable in the first year with a similar median RFS of 11 months and 10 months after DA and IMA, respectively. However, a separation of RFS curves developed with longer follow up, resulting in 1-year RFS rates of 45% versus 46%, but 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS for all randomized pts was 10 months in both arms; 1-year and 3-year OS rates were 45% and 19% after DA versus 44% and 19% after IMA (p=0.513). Conclusion: The results indicate that elderly AML pts benefit from a dose escalation of cytarabine in induction therapy by significantly higher CR rates and similar toxicity compared to a standard 7+3 approach. In our trial, this did not translate into a survival advantage, most likely due to differences in consolidation treatment of the respective treatment arms. In combination with an effective consolidation strategy such as high-dose cytarabine or allogeneic transplantation, our current results favor the use of intermediate dose cytarabine in induction for pts with a curative AML treatment approach. Figure 1. CR rates depending on induction treatment Figure 1. CR rates depending on induction treatment Disclosures Einsele: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Platzbecker:Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Ehninger:Cellex GmbH: Equity Ownership.

Abstract: Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts. Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented. Results: Cohort A: Median time on study was 9.9 mos (95% confidence interval [CI]: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 [46%] ). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response [PR]=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14. Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions [two pts], diarrhea [one pt] , one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six [46%] pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 [100%] pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 [100%] pts) reached MRD negative status in BM at C15. Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL. Disclosures Staber: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.