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Introduction Treatment with the BCL-2 inhibitor Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) has shown encouraging results in patients with acute myeloid leukemia (AML). In contrast to the FDA, EMA approval for unfit AML patients was given only recently, and VEN combinations have therefore often been used as off-label treatment for relapsed/refractory (r/r) AML patients. We conducted a retrospective study of 73 unfit or r/r AML patients treated with a VEN combination between 2017 and 2021 at two German university hospitals. Methods Data was collected by medical chart review and included genetics, ELN2017 risk classification, previous treatment lines, courses of VEN treatment as well as outcome. All statistical tests were performed with GraphPad Prism. The median time of follow-up was 8.3 months. Results At beginning of VEN treatment, the median age was 73 (20-85) years (Table 1). The majority of patients had a secondary (s) AML [n=34 (47%)] and was assigned to the adverse ELN2017 risk group [n=32 (44%)]. Mutations in isocitrate-dehydrogenase 1/2 genes (IDH1/2) were the most frequent alteration [n=19 (26%)]. Before VEN treatment, a total of n=58 (79%) patients had received prior treatment including intensive chemotherapy [n=36 (49%)] and allogeneic stem cell transplantation (allo-HSCT) [n=26 (36%)]. Twenty-five (34%) patients were treated with >4 cycles HMA or LDAC before VEN initiation. VEN was given as first-line treatment in n=15 (21%) patients and started during the first or second treatment cycle of HMA/LDAC. The initial VEN dosage after ramp-up during cycle 1 was in median 400mg (50-800mg). Patients received VEN in combination with azacytidine [n=34 (47%)], decitabine [n=18 (25%)] or LDAC [n=20 (28%)]. In median, patients had received 3 (1-17) VEN cycles at data cut-off. VEN was initiated after progression on HMA/LDAC treatment (>2 cycles) in n=35 (48%) patients. In most patients VEN was discontinued or dose-adjusted during treatment [cycle 1 n=37 (51%), after cycle 1 n=43 (59%)]. Response assessment was available for n=58 (79%) patients, of which n=18 (25%) achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi), n=24 (33%) a partial remission (PR) or stable disease (SD), and n=16 (22%) were refractory to VEN combination treatment. The overall response rate (ORR) including CR/CRi/PR patients was 47% and not influenced by age or previous treatments including allo-HSCT and HMA pretreatment. Achievement of CR/CRi was significantly better in patients with IDH1/2 and/or NPM1 mutations (Figure 1). The median overall survival (OS) of the entire cohort was 6.5 months. OS was significantly better in patients achieving a CR/CRi (20.3 months) as compared to patients with PR/SD/RD. (p=65 years), ELN2017 risk group or previous HMA treatment. OS was however significantly longer in patients harboring NPM1 and/or IDH1/2 mutations (p=0.016; Figure 2 D). Conclusions Our real-world analysis demonstrates that VEN combination treatment is feasible and effective also in r/r AML patients. Response rates and survival were lower than in patients treated with VEN combinations in first line (DiNardo, NEJM 2020) and in our cohort highly influenced by the number of previous treatment lines. As in patients treated with VEN combinations at fist line, the NPM1 and IDH1/2 genotype was associated with better response and survival. Further studies with larger cohorts are needed to investigate the role of VEN combinations in r/r AML. Figure 1 Figure 1. Disclosures Westermann: Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Novartis: Consultancy, Honoraria; BMS: Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria. Bullinger: Seattle Genetics: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Menarini: Consultancy; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Hexal: Consultancy. Keller: Abbvie: Other: Advisory Role. Krönke: BMS/Celgene: Other: Advisory board; Abbvie: Other: Advisory board. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. OffLabel Disclosure: Venetoclax was used "off-lable" in unfit and relapsed/refractory AML patients in combination with HMA/LDAC.

Treatment recommendations for cytoreductive treatment of patients with polycythemia vera (PV) are well established. However, the clinical use and limitation of phlebotomies remain a matter of current debate (Barbui et al, Leukemia, 32; Heidel et al, Leukemia, 32). While multicenter trials investigating therapeutic strategies for PV have been conducted at specialized academic centers, the majority of patients is treated in an outpatient (ambulatory) setting. The aim of this study is to evaluate the 'real live' situation especially in regard to the use of phlebotomy and cytoreductive therapy in a cohort of 1500 patients from a survey conducted at private practices and primary care centers. Eligible centers treating patients with MPN in Germany were recruited to participate in a paper-pencil based ongoing survey conducted from December 2018 and planned until December 2019. Hematologists were asked to report from patient charts. Descriptive analyses were conducted to assess for therapeutic interventions and outcomes and examined by reported prognostic risk scores, symptom scores, and clinical response criteria. For this interim analysis (data cutoff on May 31, 2019) a total of 11 centers participated in a retrospective survey and provided data on 434 patients. Gender was balanced with 211 (48.6%) male and 223 (51.4%) female patients. Most patients were of older age (mean 71.4 years; 62.7 years at diagnosis and 63,4% over the age of 60), which is a main risk factor according to published criteria (Tefferi et al, Am J Hematol, 94). 154 patients (35.5%) had a disease history of more than 10 years, 95 pts (21.9%) 6 to 10 years and 42.6% less than 6 years. Thromboembolic complications were reported in 100 patients (23.0%) at time of diagnosis and for 61 (14.1%) during treatment. Additional cardiovascular (CV) risk-factors were reported for 320 patients (73.7%), whereas 107 (24.7%) had none (and no data available in 1,6% (n=7) of cases). Hypertension was the most prevalent CV risk factor with 86.9% (n=278) affected, followed by hypercholesteremia 18.8% (n=60), diabetes mellitus 16.2% (n=52) and smoking 15.9% (n=51). Phlebotomy was the primary therapy in 301 patients (69.4%). Of those, 83 (27.6%) received 1-3 phlebotomies/year, 113 (37.5%) 4-6/year, 71 (23.6%) 7-12 times/year and 8 pts (2,6%) >13 times/year. Main triggers to start pharmacologic cytoreduction included the presence of high-risk criteria (53.2%) and insufficient disease control (22.6%). Of note, asymptomatic iron deficiency (5.6%), symptomatic iron deficiency (9.3%) and intolerance to phlebotomy (5.3%) have been reported in a significant number of patients and contributed to the limitation of phlebotomy treatment. Choice of cytoreductive agents included hydroxycarbamide (n=320; 73.3%), JAK-inhibitors (n=80, 18.4%), Interferon alpha (n=15; 3,5%), IMIDEs (n=2; 0.5%) and other cytoreductive agents (n=6; 1.4%). While 11 patients (2.5%) required combination of cytoreductive agents, 137 (31.3%) patients had a persistent need for phlebotomy. In summary, the patient population investigated here was older than in published large multicenter trials. Age was the main factor accounting for the majority of patients being categorized as 'high risk'. Although the majority of patients (>60%) presented as 'high risk' according to international guidelines, 69.4% of patients received phlebotomy as primary therapeutic approach, in part at high frequency (>25% with more than 7 phlebotomies per year). The low number of primary cytoreductive treatment and occurrence of symptomatic iron deficiency in 9.3% and of intolerance in 5.3% of patients indicates the need to reconsider indication and limitations of phlebotomy. We conclude that phlebotomy as a prophylactic measure of risk reduction should result in mild iron-deficient erythropoiesis and hematocrit control without inducing a severe iron-deficiency syndrome as indicated by increased levels of soluble transferrin-receptor or Zn-protoporphyrin. Pharmacologic cytoreduction is necessary for high risk patients older than 60 years or with previous thromboembolic complications. For patients, who require permanent phlebotomies at high frequency for sufficient hematocrit control ( Disclosures Wunschel: Novartis Inc.: Employment. Hochhaus:MSD: Research Funding; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Heidel:Novartis: Research Funding.

Background: Management of anemia is a common therapeutic challenge in patients with myelodysplastic syndromes (MDS). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label study to evaluate the effects of luspatercept in patient (pts) with low-intermediate risk MDS. Endpoints included erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, safety, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), no prior HMA, and no current lenalidomide or erythropoiesis-stimulating agent (ESA). An expansion cohort of up to 56 patients was added to this phase 2 study to evaluate response to luspatercept in pts who do not qualify for the phase 3 MEDALIST trial (for RS+ positive patients with baseline EPO ≥ 200 U/L and ≥ 2U RBC/8 weeks). These include pts with low transfusion burden (< 4U RBC/8 weeks) who are either 1) ring sideroblast (RS)+ (≥ 15% RS in bone marrow) with baseline EPO ≤ 200 U/L and no prior ESA use, or 2) RS- with any baseline EPO level and any prior ESA use. Patients are treated with 1.0 mg/kg of luspatercept every 3 weeks for up to 5 doses, with titration up to 1.75 mg/kg. Patients may rollover to an open-label extension study for up to an additional 2 years of treatment. Results: Results for the initial patient cohorts have demonstrated a high proportion of HI-E and RBC-TI responses in RS+ patients. Data for the additional ESA-naïve RS+ patients with low EPO levels and RS- patients with 3 months of treatment will be presented at the meeting. Conclusions: Erythroid response to luspatercept has been demonstrated in RS+ patients with lower-risk MDS and is being explored in ESA-naïve RS+ patients with low EPO levels and RS- patients. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Donovan: Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Background: Management of anemia is a common therapeutic challenge in patients with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label, long-term extension study to evaluate the effects of luspatercept in patients (pts) with low-intermediate risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), ESA refractory or EPO > 500 U/L, no prior HMA, and no current lenalidomide or ESA. Luspatercept was administered SC every 3 wks for up to 5 doses in the base study (NCT01749514), including 7 dose escalation cohorts (n=27 total, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, starting dose 1.0 mg/kg, max 1.75 mg/kg). A 2-year extension study (n=32) is ongoing (NCT02268383). Results: Data (as of 4 Mar 2016) were available for the 32 extension study pts. Of these, 13 pts received < 4U RBC/8 weeks pretreatment (low transfusion burden, LTB) and 19 pts received ≥ 4U RBC/8 weeks (high transfusion burden, HTB). Median age was 72 yr (range 29-90 yr), 59% had prior ESA. Median Hgb for LTB pts was 8.5 g/dL (range 6.4-10.1 g/dL) and median RBC transfusion burden for HTB pts was 6 U/8 weeks (range 4-14 units). 91% pts were RS+ (≥ 15% RS in bone marrow). IWG HI-E was achieved in 11/13 (85%) LTB pts and 15/19 (79%) HTB pts. 11/22 (50%) pts with at least 2 units transfused in 8 weeks prior to dosing with luspatercept achieved RBC transfusion independence for at least 8 weeks. The range of transfusion independence was 9 to 80+ weeks, with most responders still receiving treatment. IWG HI-E response rates were 83% for RS+ pts, 90% for EPO < 200 U/L, 86% for EPO 200-500 U/L, and 50% for EPO > 500 U/L; 85% for ESA-naïve and 79% for those who had prior ESA treatment. RBC transfusion independence was achieved in 58% for EPO < 200 U/L, 50% for EPO 200-500 U/L, and 33% for EPO > 500 U/L. Luspatercept was well tolerated, with 3 related grade 3 adverse events of myalgia, worsening of general condition, and blast cell count increase. The most common related AEs (≥ 2 pts in both base and extension studies) were fatigue, bone pain, diarrhea, myalgia, headache, hypertension, and injection site erythema. Conclusions: Long-term treatment with luspatercept was well tolerated and led to erythroid response in 81% of low-intermediate risk MDS pts who enrolled into the extension study. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Platzbecker: Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Donovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Background: Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis. Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting ineffective erythropoiesis. Aims: This completed, 3-month, phase 2, multicenter, open-label study evaluated the effects of luspatercept on anemia in patients with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response of increased hemoglobin (Hb) in low transfusion burden (LTB) patients ( Methods: Inclusion criteria include age ≥ 18 yr, anemia defined as being HTB or LTB with Hb 500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. Luspatercept was administered once every 3 weeks by SC injection in sequential cohorts (n=3-6 each) at dose levels ranging from 0.125 to 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort with a starting dose level of 1.0 mg/kg was enrolled with individual patient dose titration allowed. Patients completing this study were eligible to enroll into the PACE-MDS extension study. Results: Enrollment is complete for 27 patients in the dose escalation cohorts and 31 patients in the expansion cohort (total n=58). Preliminary safety and efficacy data (as of 17-Apr-2015) were available for 49 patients (22 female/27 male, 17 LTB/32 HTB). Final 3-month data for all 58 patients will be presented. Median age was 71 years, 61% had prior ESA therapy, and 18% had prior lenalidomide. Forty (83%) patients had ≥15% ring sideroblasts (RS+) in the bone marrow. The median baseline Hb for LTB patients was 8.7 g/dL (range 6.8-10.1 g/dL). The median number of RBC units transfused over 8 weeks prior to treatment for HTB patients was 6 units (range 4-14 units). Luspatercept was generally well-tolerated. In patients (n=40) receiving 0.75-1.75 mg/kg, 48% of patients responded per IWG HI-E (Hb increase ≥1.5 g/dL for LTB patients or reduction of ≥ 4 RBC units/8 weeks for HTB patients). Higher response rates were observed in RS+ patients, including patients with EPO ≥ 200 U/L; patients with splicing factor (SF) mutations present (primarily SF3B1) had 60% response rate (see Table). Of the patients who received RBC transfusions prior to luspatercept treatment (range 2-14 units/8 weeks), 11 of 30 (37%) patients were transfusion-free for ≥8 weeks during the 12 week treatment period. Neutrophil responses (IWG HI-N) were seen in 4 of 8 (50%) patients with baseline neutrophil count The relationship of erythroid response to bone marrow erythroid cellularity, morphology and characteristics, comprehensive gene mutation profile, GDF15, and other biomarkers of ineffective erythropoiesis will be presented. Conclusions: Based on these data, treatment with luspatercept in lower risk MDS patients at therapeutic dose levels for 3 months led to a high response rate for increased Hb levels or decreased transfusion burden, including transfusion independence, with a favorable safety profile. Ring sideroblasts, splicing factor gene mutations and other biomarkers of ineffective erythropoiesis may help define a MDS population most likely to respond to luspatercept treatment. Phase 3 studies in patients with anemia due to lower risk MDS are planned. Disclosures Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Boehringer: Research Funding. Ottmann:BMS: Honoraria, Research Funding; Novartis: Consultancy. Hankin:Acceleron: Employment. Wilson:Acceleron: Employment. Zhang:Acceleron: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Attie:Acceleron: Employment.

Background: Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis. Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting the ineffective erythropoiesis. Aims: This is an ongoing, phase 2, multicenter, open-label, 24-month extension study (following a 3-month base study) to evaluate the longer-term effects of luspatercept on anemia in patients (pts) with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response of increased Hb in low transfusion burden (LTB) pts ( Methods: In the base study, eligibility criteria included age ≥18 yr; anemia defined as being HTB or LTB with Hb 500 U/L or nonresponsive/refractory to ESAs; no prior azacitidine or decitabine; and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. Luspatercept was administered once every 3 weeks by SC injection in sequential cohorts (n=3-6 each; total n=27) at dose levels ranging from 0.125 to 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=31) with a starting dose level of 1.0 mg/kg was enrolled with individual pt dose titration allowed. Patients completing the 3-month base study were eligible to enroll into this extension study (with or without interruption ≥3 months) where they continue to receive luspatercept every 3 weeks for up to 24 months. Results: Enrollment is complete for this extension study (n=32). Preliminary safety and efficacy data (as of 17-Apr-2015) were available for 22 of 32 patients (9 LTB/13 HTB) with continuous luspatercept treatment for a median of 8 cycles (range 5-12). Median age was 70.5 yr, 64% had prior ESA therapy, and 18% had prior lenalidomide. All 22 patients had ≥15% ring sideroblasts (RS+) in bone marrow. Eight of 9 (89%) of LTB patients achieved an IWG HI-E response for hemoglobin increase (≥1.5 g/dL for ≥8 weeks). Mean change in hemoglobin in these patients exceeded 1.5 g/dL for a median duration of 17 weeks (range 5-22 weeks) as of the data cutoff date in this ongoing study. Ten of 13 (77%) of HTB patients achieved an IWG HI-E response (reduction of ≥4 RBC units transfused over 8 weeks). Of the 14 patients who received transfusion of ≥2 RBC units over 8 weeks prior to the start of treatment, 6 (43%) patients achieved transfusion independence for at least 8 weeks (median 23 weeks, range 10-30 weeks as of the data cutoff date). All 6 patients were continuing to receive treatment as of the data cutoff date; updated data for duration of response will be presented. Luspatercept has been generally well-tolerated in the extension study, with no grade 3 or higher related adverse events. Conclusions: Based on preliminary data from the 24-month extension study in lower risk MDS patients, luspatercept treatment led to sustained HI-E response for increased Hb levels, decreased transfusion requirement or transfusion independence in the majority of patients, with a favorable safety profile. Phase 3 studies in patients with anemia due to lower risk MDS are planned. Disclosures Platzbecker: Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ottmann:BMS: Honoraria, Research Funding; Novartis: Consultancy. Hankin:Acceleron: Employment. Wilson:Acceleron: Employment. Zhang:Acceleron: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Attie:Acceleron: Employment.

Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-ß superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. RAP-536 (murine version of ACE-536) reduced Smad 2 signaling, increased hemoglobin (Hb) levels and decreased bone marrow erythroid hyperplasia in a mouse model of MDS (Suragani R et al., Nature Medicine 2014). In a healthy volunteer study, ACE-536 was well-tolerated and increased Hb levels (Attie K et al., Am J Hematol 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 on anemia in patients with Low or Int-1 risk MDS who have either high transfusion burden (HTB, defined as ≥4 units RBCs/8 weeks prior to baseline) or low transfusion burden (LTB, defined as Methods.Inclusion criteria included Low or Int-1 risk MDS, age ≥ 18 yr, anemia (defined as either being HTB patient or having baseline Hb < 10.0 g/dL in LTB patient), EPO >500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. In the dose escalation phase, ACE-536 was administered by subcutaneous (SC) injection once every 3 weeks in 7 sequential cohorts (n=3-6) at dose levels of 0.125, 0.25, 0.5, 0.75, 1.0, 1.33 and 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=30) is planned, and all patients completing this study may enroll in a 12-month extension study. Results. Preliminary data were available for 26 patients (7 LTB/19 HTB) as of 18 Jul 2014. Median age was 71 yr (range: 27-88 yr), 50% were female, 54% had prior EPO therapy and 15% had prior lenalidomide. 69% were WHO subtype RCMD, and the remaining patients were del(5q), RARS, or RAEB-1. Mean (SD) baseline Hgb for the LTB patients (n=7) was 9.1 (0.4) g/dL. Mean (SD) units RBC transfused in the 8 weeks prior to treatment was 0.9 (1.1) units for the LTB patients and 6.3 (2.4) units for the HTB patients. Two of the 7 LTB patients had an increase in mean Hb ≥1.5 g/dL over 8 weeks compared to baseline. Mean maximum Hb increase in the LTB patients was 0.8, 1.0, 2.2, and 2.7 g/dL in the 0.125 (n=1), 0.25 (n=1), 0.75 (n=3), and 1.75 (n=2) mg/kg dose groups, respectively. Six of the 7 LTB patients achieved RBC transfusion independence (RBC-TI) for ≥8 weeks during the study. Six of the 19 HTB patients had a ≥4 unit or ≥50% reduction in RBC units transfused over an 8-week interval during the treatment period compared to the 8 weeks prior to treatment; five of these 6 patients achieved RBC-TI ≥ 8 weeks during the study (range 71-152 days). Increases in neutrophil count following study drug administration were observed in some patients. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent adverse events regardless of causality were: diarrhea (n=4, grade 1/2), bone pain, fatigue, muscle spasms, myalgia, and nasopharyngitis (n=3 each, grade 1/2). Conclusions. Based on preliminary data in Low or Int-1 MDS patients, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels or decreased transfusion requirement, with a favorable safety profile. These data strongly support further evaluation of longer-term treatment with ACE-536 in patients with MDS. Disclosures Platzbecker: Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Goetze:Celgene Corp: Honoraria; Novartis Pharma: Honoraria. Radsak:Celgene: Research Funding. Hankin:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

Abstract 3125 Background: PCNSL is a rare form of extranodal diffuse large B-cell lymphoma (DLBCL). Relapses after initial therapy are usually within the CNS. Systemic relapses (SR) have been reported only occasionally. We conducted a systemic analysis of immunocompetent patients with PCNSL und SR using both clinical data and tumor samples at first diagnosis and SR to determine clonal relatedness. Methods: Records of patients included in a multicenter therapy trial (n=411) and all PCNSL patients treated at our institution outside the trial after 1993 (n=39) were reviewed for SR. PCR analysis of the rearranged Ig heavy-chain (IgH) and light-chain (IgL) genes was performed according to the BIOMED-2 protocol. Result: All patients had received high-dose methotrexate based chemotherapy with our without adjuvant whole brain irradiation as first line therapy. Of 450 patients 26 (5.8%) were identified with SR. Median time from PCNSL diagnosis to SR was 14.5 months (range 2–61). SR was extranodal in 22 (85%) patients: testicular n=3, gastric n=3, mamma n=3, liver n=2, bone/bone marrow n=3, intestinal n=1, [sub-]cutaneous/muscular n=5, pancreatic n=1, pulmonary n=1. Four patients had concomitant CNS relapse. Median overall survival from diagnosis was 38 months, from SR 9.8 months. Causes of death were SR in 13, CNS relapse in 3, toxicity of chemotherapy in 3 and unknown in 1 patients; 6 patients were alive at last follow up. All 26 patients initially had DLBCL. SR was biopsied in 20 patients: 19 had DLBCL, 1 a Burkitt-like DLBCL. DNA of 7 patients was sufficient for PCR analysis. The same clone was found in the CNS and SR in 4 patients, in 3 patients the clones were different. Clonally related SR occurred after 4, 8, 14 and 25 months; the unrelated SR after 30, 35 and 36 moths.PCR products in 2 of 4 clonally related samples were suitable for sequencing. One case exhibited 6 identical somatic mutations in both biopsies. The second case harbored 35 mutations in the CNS sample and 45 in the SR sample. Here 26 mutations were identical in both samples, 3 involved different nucleosides, 16 were only present in SR, and 6 mutations exclusively present in the CNS sample. Conclusion: SR is a rare and frequently fatal complication in PCNSL. The localization of SR is predominantly extranodal. A proportion of SR is not clonally related to the primary tumor and then most likely represent a secondary lymphoma. In clonally related SR the presence of somatic mutations unique to the CNS tumor and the SR might be explained by a common ancestor, whose localization however remains unknown. Disclosures: No relevant conflicts of interest to declare.

Introduction: The frequency of meningeal dissemination (MD) in primary central nervous system lymphoma (PCNSL) reported in the literature differs. The optimal management and the prognostic impact of MD have not been defined. Methods: Data on MD from all 92 immunocompetent patients primarily diagnosed with PCNSL at our institution between January 1994 and February 2007 were retrospectively analysed for MD evaluation. All patients received cranial MRI or CT, and in 71 patients CSF was obtained by lumbar puncture. High-dose methotrexate was the intended treatment in all patients. Results: Cerebrospinal fluid (CSF) was obtained by lumbar puncture in 71 patients (median age 62 years) of a total of 92 patients with PCNSL. Cytomorphologic CSF examination was performed in 63, immunophenotyping in 32 and PCR of the CDR3 region in 37 patients. Eight of 63 patients (13%) had positive cytomorphology, one of 32 (3%) positive immunocytology and 6 of 37 (16%) had monoclonal B-cells on PCR analysis. Evidence of MD on MRI or CT was found in three of the 71 patients (4%). Altogether, 11 (16%) patients had evidence of MD diagnosed by either of the methods used. Median CSF cell count was 5/μl (range, 0–237; n=66), and median protein concentration 76 mg/dl (range, 93–4117; n=55). An elevated cell count (>5/μl) was found in 27 (41%) patients, an elevated protein (>45 mg/dl) in 44 (80%). No significant correlation was found between proof of MD and CSF pleocytosis or elevated protein. Patients with MD did not differ from other patients with respect to age, gender, clinical presentation, performance status, CSF cell count and protein concentration, number of intracerebral lesions, lesion location or histology. After a median follow-up of 56 months, median EFS was 26 (95% CI, 4.3 to 47.7) months for MD patients and 34.1 (95% CI, 26.2 to 42) months for those without MD, p=0.26 (log-rank). Of 21 patients with relapse after initial treatment response, 16 had isolated cerebral relapse, one isolated meningeal relapse, two systemic relapse (one with cutaneous, and one with testicular manifestation), and one concomitant systemic (lung/thoracic wall) and cerebral relapse. Of the four MD patients with relapse after initial response, three had cerebral relapse, and one had systemic (cutaneous) relapse. The median overall survival (OAS) of patients with MD was 45.5 months (95% CI, 16.6 to 74.4), of those without MD 42.5 months (95% CI, 35.8 to 49.2) (p=0.27). Conclusions: The frequency of MD detected in our cohort was low despite the use of highly sensitive diagnostic methods. No impact on either EFS or OAS was seen for MD.

Background: The mechanisms leading to development of CNS lymphoma (CNSL) are still poorly understood. Homing of malignant lymphocytes to the CNS may play an important role in the pathogenesis of CNSL. Expression of chemokine receptors CXCR4 and CXCR5 has been shown on tumor cells of primary CNSL. In this study we examined the level of chemokines CXCL12 and CXCL13 which are ligands of CXCR4 and CXCR5 respectively in the CSF of CNSL patients and compared it to non-CNSL controls. Methods: Lumbar CSF and peripheral blood from 16 patients with primary and one with secondary CNSL, as well as control CSF from 8 patients with hydrocephalus, glioblastoma, peripheral lymphoma without CNS involvement or unspecific neurological symptoms were collected, and after centrifugation supernatant and serum were cryopreserved at −80°C until analysis. Chemokine concentrations were measured using commercially available ELISA kits (CXCL13/BCA-1 and CXCL12/SDF-1α Quantikine Immunoassay, R&D Systems, Minneapolis) according to the manufacturer’s instructions. Results were confirmed by duplicate measurements. Results: 22 CSF samples and 11 serum samples from CNSL patients and nine CSF samples from controls were evaluated (see table). There was no correlation between serum and CSF chemokine levels in CNSL patients. Median concentrations of both CXCL12 and CXCR13 were higher in patients with CNS lymphoma compared to controls, CXCL13 being significantly raised (p=0.0019). In one CNSL patient three serial CSF samples could be analysed and a ten-fold decrease of CXCL12 during succesfull chemotherapy was found whilst concentration of CXCL13 remained stable. Conclusion: CXCL12 and CXCL13 can be measured in the CSF of CNS lymphoma patients at higher concentration as compared to non-CNSL patients. Analysis of a larger population is warranted in order to define the role of these chemokines in CNSL and to establish their value for diagnosis and follow up. Serum CSF CNSL patients CNSL patients controls p range median (range) median (range) CXCL12 1788–2933 pg/ml 481 (55–2079) pg/ml 115 (0–2442) pg/ml 0.067 CXCL13 36–657 pg/ml 457 (18–657) pg/ml 16.9 (0.6–187) pg/ml 0.00019

Background This is a retrospective, long-term single-center analysis of immunocompetent patients with PCNSL treated at our institution. Methods All 72 consecutive patients diagnosed with PCNSL between January 1994 and February 2005 were scheduled to receive high-dose methotrexate (HDMTX; 1.5–4 g/m2) based chemotherapy. Results The median age of the patients was 62 years, the median Karnofsky performance status (KPS) was 70%. Twelve patients did not receive HDMTX based chemotherapy due to poor physical condition or renal insufficiency. Of 60 patients treated with HDMTX based chemotherapy, 9 were followed by whole brain irradiation (WBI). Of 54 patients evaluable for response 35 (65%) responded (52% CR and 13% PR), and 19 (35%) did not. At a median follow-up of 58.7 months, median progression-free survival (PFS) was 9 months, and median overall survival (OAS) was 41.4 months. Eight patients have survived 60 months or longer (median age 48, range 19–76; median KPS 80, range 40–100), 5 of whom relapsed after primary therapy at a median of 5 months (range, 3–39.7) after initial diagnosis. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognosis score, patients could be divided into three groups with significantly different OAS: 52.9 months for patients younger than 50 years, 42.4 months for patients ≥50 years and with KPS ≥70, and 5.2 months for patients ≥50 years and KPS Conclusions This study providing long-term data shows that a relatively moderate HDMTX-based chemotherapy can result in prolonged survival and probably cure even in older and early relapsing patients. However, the probability of late neurotoxicity with prolonged survival is considerable. The comparison of our results to other retrospective studies underscore the importance of treating PCNSL patients preferably at experienced institutions. The MSKCC score proved useful to predict survival.

Background: Salvage treatment has not yet been established in primary CNS lymphoma (PCNSL). The introduction of anti-CD20 monoclonal antibody rituximab expanded treatment options in systemic B-cell lymphoma. Due to its large molecular size, rituximab poorly penetrates the blood-brain-barrier (BBB) limiting its use in PCNSL. According to FDG-PET investigations, however, the BBB is initially leaky in PCNSL and reconstitutes after therapy-induced tumor shrinkage. We treated patients with relapsed/resistant PCNSL with a single course of Y-90 anti-CD20 antibody ibritumomab tiuxetan and evaluated the penetration of the antibody into the tumor. Methods: Immunocompetent patients with histologically confirmed, therapy resistant or recurrent PCNSL after at least one pretreatment, and adequate cardiac and bone marrow function were treated with rituximab 250 mg/m2 on day -7 and day 0, followed by Y-90-ibritumomab tiuxetan 15 MBq/kg IV. In three patients single photon emission computed tomography (SPECT) target imaging with gamma-emitting 111-Indium-ibritumomab tiuxetan was performed repeatedly 4 - 168 hours after Y-90-ibritumomab tiuxetan. Response evaluation by contrast-enhanced magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) was scheduled before, one month and two months after treatment as well as every three months thereafter in responders. Results: Seven patients with a median age of 46 years (range 40–63) and a median number of 4 (range 1–6) previous therapies received antibody treatment. SPECT indicated target accumulation in the tumor starting 48 hours and still ongoing 7 days after injection of 111-Indium-ibritumomab tiuxetan. Response was observed in four of seven patients: one uncertain complete response (uCR) lasting 18+ months, two CR (0.5 and one month), and one partial response (0.5 months). Relapse usually occurred distant of target lesions. Three patients had disease progression. Toxicities were leukopenia CTC grade 3/4 (n=6), pneumonia grade 3/4 (n=2) with one fatal outcome, and thrombocytopenia grade 3/4 (n=6). Conclusions: We provide first evidence of Y-90-ibritumomab tiuxetan penetration into PCNSL with target accumulation of the antibody in SPECT. However, responses were mostly of short duration in this heavily pretreated patient cohort with relapses occurring distant of target lesions. Hematotoxicity up to CTC grade 4 was the most common side-effect. Further investigation within a phase II study is warranted.