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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.

Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes.In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count13 000/μL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (200 IU/L, 200-500 IU/L, and500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383.Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration.Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing.Acceleron Pharma.

Background: Luspatercept, a first-in-class erythroid maturation agent, has been investigated in patients with LR-MDS and ring sideroblasts (RS) (MEDALIST; Fenaux and Platzbecker NEJM 2020) and in an ongoing Phase 3 trial regardless of RS status (COMMANDS, NCT03682536 ). The previously reported Phase 2 trial of luspatercept (Platzbecker Lanc Onc 2017) includes subtypes of LR-MDS with and without RS, regardless of prior ESA exposure, and various EPO levels. Aims: Evaluate the long-term safety and efficacy of luspatercept in LR-MDS. Methods: Patients were IPSS low/int-1, age ≥ 18 years, Hgb NCT01749514 ; NCT02268383 ). Results: As of 13July2019, 115 patients were enrolled, of whom 108 were treated with ≥0.75 mg/kg. 44/108 (41%) were non-RS; 47/108 (44%) had prior ESA; 45/108 (42%) had baseline transfusion burden of ≥4U RBC/8 weeks. Median duration of treatment (n=108) was 10.4 (0.7-57.3) months. IWG HI-E RR was 54% (58/108) overall; 36% (16/44) in non-RS, 68% (42/62) in RS+ (2 patients had unknown RS status); 53% (25/47) prior ESA, 54% (33/61) in ESA-naive; 54% (34/63) in 2 patients) were fatigue, headache, hypertension, arthralgia, bone pain, diarrhea, injection site erythema, myalgia, and peripheral edema. Conclusions: Consistent with previous reports, data from the long-term Phase 2 study of luspatercept in LR-MDS continues to show efficacy in a variety of subtypes and safety similar to previous and ongoing studies.

Chemoradiation is one of the therapeutic options in palliative treatment of locally advanced pancreatic adenocarcinoma, with a well-known safety profile. In this case report, we describe the treatment-related occurrence of an intrasplenic pancreatic pseudocyst which was successfully removed by gastrocystic drainage. This rare complication should be considered in the follow-up and clinical management of patients, particularly if left-sided complaints occur.

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.

Summary The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

The prognosis of patients with CNS involvement of solid tumors is poor. In these patients, systemic chemotherapy has a theoretical advantage of concurrent treatment of systemic disease and reduced risk of neurotoxicity. Here, we report on the efficacy and toxicity of topotecan/ifosfamide (TOPO/IFO) combination chemotherapy in patients treated for CNS involvement of different solid malignancies. Fourteen patients with CNS manifestations (seven with brain metastases, two meningeal carcinomatosis, and five both) of solid tumors (seven with breast cancer, six lung cancer, and one unknown primary cancer) received TOPO/IFO treatment. Eleven patients each were pretreated with 1-6 systemic therapy regimens and whole-brain irradiation. Patients received a total of 34 (median 2) TOPO/IFO cycles. TOPO dosage was 3.6 mg/m(2) (1.2 mg/m(2), days 1-3) and IFO dosage 3,000 mg/m(2) (1,500 mg/m(2), days 1-2) per cycle. Of 12 patients with brain metastases, one patient had partial remission, three stable disease, two progressed, and six had no radiologic CNS response evaluation. Response of meningeal carcinomatosis was found in two and progressive disease in two (three patients not evaluated). Neurologic improvement or stabilization was observed in six of twelve evaluable patients. No systemic tumor response was seen in seven evaluated patients. Grade 3/4 toxicities in eleven evaluable patients were leukopenia (n = 9), infection (n = 6), and thrombopenia (n = 5). Median time to treatment failure was 43 days and median overall survival 107 days. Symptom control was frequently achieved with TOPO/IFO systemic chemotherapy despite a low objective response rate. The feasibility of this treatment is impaired by severe hematotoxicity.

7018Background: Luspatercept (ACE-536) is a TGF-β family ligand trap promoting late-stage erythroid (E) differentiation and increases in hemoglobin. Endpoints of the ongoing, phase 2, open-label st...

Background: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. Patients and methods: A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53-or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion. Results: The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms. Conclusions: These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.

The aim of this study was to examine the penetration of ifosfamide (IFO) and 4-hydroxy-ifosfamide (4-OH-IFO) into the CSF of human adults and to evaluate the influence of blood–CSF barrier (BCB) function. In 12 adult patients with a malignant CNS disease treated with IFO 1,300–2,000 mg/m2/d as a 3-hour intravenous infusion, 17 CSF samples were collected within 10 min after the end of IFO infusion. In 8 of these patients, the CSF was obtained in up to 5 sequential 2-ml portions to detect a potential caudocranial concentration gradient. Additionally, blood was collected before treatment and immediately following IFO infusion. IFO was detected in all 17 CSF samples at a median concentration of 79.24 μmol/l (39.27–176.73) and a median CSF/plasma ratio of 0.38 (0.18–0.72). 4-OH-IFO was detected in 11 CSF samples from 7 patients at a median concentration of 4.1 μmol/l (2.44–36.03) and a median CSF/plasma ratio of 3.07 (0.62–29.12). 4-OH-IFO was undetectable in 6 CSF samples from 5 patients and in one plasma sample. Both CSF drug concentrations and their CSF/plasma quotients neither correlated with steroid comedication nor with albumin quotients (QAlb). Both IFO and 4-OH-IFO can penetrate into the CSF of human adults without a correlation to CSF turnover. In contrast to IFO, 4-OH-IFO CSF penetration is not reliable with levels ranging between undetectable and exceeding those in the corresponding plasma.

The frequency of meningeal dissemination (MD) in primary CNS lymphoma (PCNSL), its prognostic impact, and optimal management have not been defined thus far. In 69 of 92 (75%) immunocompetent patients, primarily diagnosed with PCNSL at our institution between January 1994 and February 2007, cerebrospinal fluid was analyzed for MD. MD was found by cytomorphology in 7/63 (11%), by immunophenotyping in 1/32 (3%), and by PCR of the IgH CDR III region in 6/37 (16%). Neuroradiologic examination revealed MD in 3 of 69 patients (4%). Median event-free survival (EFS) of patients with MD diagnosed by any of the methods was 26 months, of those without MD 34.1 months (P = .24); median overall survival (OAS) of these two patients' groups was 45.5 and 42.5 months, respectively (P = .34). Patients with cytomorphologic proof of MD had a median EFS of 15.4 months and OAS of 18.5 months, those without MD 34.3 and 45 months (P = .018 and .017, respectively). We found a low frequency of MD despite the use of putatively sensitive diagnostic methods. No impact on outcome was seen for MD, diagnosed by any of the methods used; however, patients with cytomorphologic proof of MD had a significantly shorter median EFS and OAS.

Background: Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity. Methods: This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m−2. Results: The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased γ-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m−2). The MTD of weekly sagopilone was therefore established as 5.3 mg m−2. Stable disease was the best overall response (n=3). Microtubule bundle formation in peripheral blood mononuclear cells increased post-treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release. Conclusion: Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials.

Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcgamma receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200 microg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomab's mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.

Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with preferential binding to activating Fcgamma type I/III-receptors, resulting in the formation of a tri-cell complex among tumour cell, T cell and accessory cell. Recently, the antibody demonstrated antitumour efficacy against HER2/neu low-expressing tumours resistant to trastuzumab. Data from a completed Phase I study in metastatic breast cancer patients indicates strong immune responses. Owing to efficient tumour cell destruction by humoral and T-cell-dependent mechanisms, differing from conventional HER2/neu directed treatments, and a potential for long-lasting antitumour immunoreactivity, ertumaxomab is at present investigated within Phase II studies enrolling metastatic breast cancer patients even without HER2/neu gene amplification.

International audience; Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m of MTX (4 h infusion on day 1) and 1.5–2 g/m/day of IFO (3 h infusion on days 3–5). The study included 20 patients with a median age of 65 years (range, 30–83) and CNS relapse of a malignant lymphoma. Seventeen patients had been pretreated with up to two chemotherapy regimens. The objective response rate was 90% with 12 complete or unconfirmed complete (CR and CRu) and six partial remissions. All patients had at least stabilization of their neurological symptoms. Myelosuppression was the most common toxicity. The median follow-up time was 14.9 months. The median time to neurological progression was 8.9 months. Twelve patients received subsequent therapy, including high-dose chemotherapy with autologous stem cell transplantation in five cases. The median overall survival was not reached. Systemic chemotherapy with HDMTX/IFO is a feasible and promising treatment modality for CNS relapse of a malignant lymphoma.

Most cancer vaccination trials have been performed in human leukocyte antigen (HLA)-A2 positive populations. Some studies have used HLA-A2 negative patients as control group. However, HLA-type and HLA-expression can interact with tumor biology and possibly affect prognosis. HLA-A2 negative patients might constitute an inadequate control group.Patients with colorectal cancer were serologically analyzed for HLA-A2 expression. Patients were evaluated for tumor stage, grading, tumor location. Overall survival (OAS) of HLA-A2 positive and HLA-A2 negative patients was compared.One hundred forty-four patients were evaluable (50% HLA-A2+). Median age was 62 years. UICC stage III or IV: 45.8%. Gender, location, and UICC stage were equally distributed between HLA-A2 subgroups. HLA-A2 positive patients more frequently had grade 3 histology (27.8% vs 13.9%) and chemotherapy (62.9% vs 45.6%). At a median follow-up of 75.8 months, median OAS for the entire study population was 123.3 months, 5-year OAS was 77.5%. No statistically significant difference in OAS was observed between HLA-A2 positive and negative patients (116.5 vs 157 months, 5-year-OAS 74.1+/-11.6% vs 81+/-11.6%, p=0.46). Expectedly, patients with UICC stage I and II disease lived significantly longer than patients with stage III and IV (5-year OAS 94.3% vs 53.4%; p0.001). A significantly superior OAS was also found for women, independent of stage or HLA status.HLA-A2 positive patients exhibit poorer tumor differentiation. This might account for a non-significant difference in OAS. The use of HLA-A2 negative patients as control cohort in CRC vaccinations would rather underestimate potential treatment-related survival effects. Therefore, we suggest they constitute a valid auxiliary control group.

Die Blut-Hirn-Schranke hemmt die Penetration von Zytostatika in das Hirnparenchym. Aufgrund des Fehlens dieser Schranke sind Hirnmetastasen jedoch grundsatzlich einer systemischen Chemotherapie zuganglich. Lediglich kleinere Tumorzellabsiedelungen mit wahrscheinlich intakter Blut-Hirn-Schranke sind als relativ geschutzt anzusehen. Zusatzlich ist die Behandlung von Hirnmetastasen durch die Chemoresistenz des Tumors und einen haufig schlechten Allgemeinzustand der betroffenen Patienten limitiert. Neue Zytostatika sind durch ihre biochemischen Eigenschaften oft besser in der Lage, in das Hirngewebe vorzudringen. „Targeted drugs“, wie beispielsweise Tyrosinkinaseinhibitoren, besitzen zudem selektivere Wirkmechanismen, potenziell eine synergistische Aktivitat in Kombination mit Chemotherapie und haufig einen besseren therapeutischen Index. Ihre Wirksamkeit wird derzeit in klinischen Studien uberpruft.

BACKGROUND. This retrospective, single-center study assessed the feasibility, outcome, and late side effects of the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL) at the authors' institution. METHODS. All 72 consecutive patients diagnosed with PCNSL between January 1994 and February 2005 were scheduled to receive high-dose methotrexate (HDMTX)-based chemotherapy. RESULTS. The median age of the patients was 62 years and the median Karnofsky performance score (KPS) was 70. Twelve patients did not receive HDMTX-based chemotherapy because of poor physical condition or renal insufficiency. Of the 60 patients treated with HDMTX-based chemotherapy, the treatment of 9 was followed with whole-brain irradiation. Of 54 patients who were evaluable for response, 35 (65%) responded (52% with a complete response and 13% with a partial response), and 19 patients (35%) did not. At a median follow-up of 58.7 months, the median progression-free survival was 9 months and the median overall survival (OAS) was 41.4 months. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognosis score, patients could be divided into 3 groups with significantly different OAS: 52.9 months for patients aged 70, and 5.2 months for patients aged ≥50 years and with a KPS

Purpose To search for subclinical systemic disease in bone marrow and peripheral blood in patients with primary CNS lymphoma (PCNSL) to elucidate whether extracerebral relapse may represent a sequel of initial occult systemic disease rather than true extracerebral spread. Patients and Methods Bone marrow and peripheral-blood specimens of 24 PCNSL patients were examined using polymerase chain reaction (PCR) for analysis of clonally rearranged immunoglobulin heavy-chain (IgH) genes. Results Identical dominant PCR products were found in bone marrow aspirates, blood samples, and tumor biopsy specimens of two patients, indicating that the same tumor cell population is present in the CNS and in extracerebral sites. Follow-up IgH PCR performed in one of these patients in complete remission 24 months after diagnosis yielded a persistent monoclonal product in the blood. An oligoclonal IgH rearrangement pattern was found in the tumor specimen of two other patients, whereas bone marrow and blood samples demonstrated the same dominant PCR products. Follow-up PCR showed a persistent monoclonal amplificate in blood in one of these patients 27 months after diagnosis. Conclusion It could be demonstrated for the first time that subclinical systemic disease can be present in PCNSL patients at initial diagnosis. Our findings may have an impact on the understanding of PCNSL pathogenesis and the extent of staging and treatment.

Purpose: Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with selective binding to activatory Fcγ type I/III receptors, resulting in the formation of a tri-cell complex between tumor cells, T cells, and accessory cells. Patients with metastatic breast cancer were enrolled into a multicenter phase I dose-escalating trial.Experimental Design: Three ascending doses of ertumaxomab (10-200 μg) were administered i.v. on day 1, 7 ± 1, and 13 ± 1. Safety and tolerability were the primary objectives. Secondary objectives were antitumor activity and different immunologic variables.Results: Fifteen out of 17 enrolled patients completed the study. One hundred micrograms was identified as the maximal tolerable single dose. Most drug-related adverse events were mild and transient including fever (94%), rigors (47%), headache (35%), nausea (29%), vomiting (29%). Grades 3 and 4 (Common Toxicity Criteria) were lymphocytopenia (76%) and elevation of liver enzymes (47%). One patient (200 μg dose) developed severe hypotension and respiratory distress syndrome, another patient (150 μg dose) developed a systemic inflammatory response syndrome and acute renal failure. Aggravation of congestive heart failure was seen in one patient with preexisting ventricular dysfunction after administration of the third dose (200 μg). All adverse events were fully reversible. Antitumor response was seen in 5 out of 15 evaluable patients (one with a complete response, two with partial responses, two with stable disease) at dose levels of ≥100 μg. Measurements of cytokines (interleukin-6, interleukin-2, tumor necrosis factor-α, and IFN-γ) suggest a strong T helper cell type 1–associated immune response. The induction of human anti-mouse/anti-rat antibodies was detected in 5 out of 16 (31%) patients.Discussion: Treatment with triple infusions of ertumaxomab yields a strong immunologic response. Doses up to 100 μg can be safely infused with close monitoring of patients. The observed clinical responses are encouraging and indicate antitumor efficacy.

Along with the establishment of more intense chemotherapeutic regimens including fludarabine for the treatment of indolent lymphoproliferative diseases like chronic lymphocytic leukemia (CLL), an increasing amount of cases with progressive multifocal leukoencephalopathy (PML) due to JC virus have been observed. We report a patient with CLL who developed PML parallel to the onset of fludarabine therapy. Spinal fluid was tested positive for JC virus. Despite virostatic treatment with cidofovir, neurologic symptoms were progressive and the disease ultimately fatal. The present case suggests that immunosuppression caused by chronic lymphoproliferative malignancies alone may be a factor in the development of PML. Chemotherapy with fludarabine may act as an additional trigger. The question remains whether serologic screening for JC virus in patients with chronic lymphoproliferative disease undergoing intense chemotherapy might be valuable once sufficient antiviral treatment has been established.

Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL+disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23–1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL+leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.

An isolated CNS relapse is rarely seen in acute myeloid leukemia. However, it has a potentially fatal clinical outcome. We herein present the case of a 39-year-old man, who presented to our emergency room with horizontal diplopic images, vertigo, bilateral deafness, and progressing somnolence. Cerebral imaging revealed cerebral and cerebellar edema and a diffuse leukoencephalopathy. With the one-year-old history of an initially successfully treated FAB-M0 acute myeloid leukemia (AML) in mind, a lumbar puncture was carried out that showed a vast number of myeloid blasts in the morphologic analysis of the cerebrospinal fluid. In conjunction with normal findings in the peripheral blood-count with differential and the bone marrow examination a diagnosis of an isolated CNS relapse of the AML was made. Cytarabine chemotherapy was initiated and the symptoms resolved rapidly. To our surprise, cerebral imaging in the course of the treatment not only showed a resolution of the brain edema but also of the leukoencephalopathy, pointing to a direct infiltration of brain parenchyma by leukemic blasts. The case highlights the relevance of the CNS as a pharmacologic "sanctuary" for tumor cells in patients that on prior treatments have not received intrathecal chemotherapy or chemotherapeutics that cross the blood-brain barrier.

Lymphoma manifestations of the dura mater are extremely rare and have mostly been attributed to extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type. We report a patient with an isolated meningeal tumor, identified as a B-cell lymphoproliferative disorder with typical B-cell chronic lymphocytic leukemia immunophenotype. Because of the subclinical detection of trisomy 3 in the bone marrow by cytogenetic analysis and interphase fluorescence in situ hybridization, CD5(+) MALT is an important differential diagnosis; however, to our knowledge, this entity has never been reported in the context of dural lymphoma.

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. Positron emission tomography (PET) with F-18-labeled fluorodeoxyglucose (FDG) provides remarkable accuracy in detection, treatment monitoring and follow-up of systemic malignant lymphoma. Its value in the management of patients with primary central nervous system lymphoma (PCNSL) is less clear. Patients and methods. In a prospective trial, 42 FDG-PET examinations were performed in ten immunocompetent patients with newly diagnosed or recurrent PCNSL before and repeatedly during and after the treatment. Brain and whole body FDG-PET were compared to brain MRI and extra-cerebral CT, respectively. Results. Before the treatment, 6 of 10 patients had congruent findings on FDG-PET and MRI of the brain. Three patients had lesions on brain MRI, not detected by FDG-PET. One patient had additional FDG-PET positive lesions inconspicuous in MRI. The follow-up suggested FDG-PET to be false positive in these lesions. After the treatment, brain PET was in agreement with MRI in 6 of 8 patients. In the remaining 2 patients there were persistent lesions in brain MRI whereas FDG-uptake was reduced to normal values. In the long-term follow-up of 5 patients (63-169 weeks), 3 patients retained normal in both PET and MRI. In 2 patients a new focal pathologic FDG-uptake was detected 69 and 52 weeks after the end of the treatment. In one of these patients, recurrence was confirmed by MRI not until 9 weeks after PET. Conclusions. Brain FDG-PET may contribute valuable information for the management of PCNSL, particularly in the assessment of the treatment response. Integration of FDG-PET into prospective interventional trials is warranted to investigate prognostic and therapeutic implications.

To assess the outcome of elderly patients with primary CNS lymphoma (PCNSL) treated within the G-PCNSL-SG-1 trial.We reviewed response, toxicity, and survival of patients with PCNSL aged 70 or more enrolled in the G-PCNSL-SG-1 trial.A total of 126 of the 526 eligible patients (24%) and 66 of 318 patients (21%) in the per protocol population were aged 70 or more. Among all eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly vs 57% in the younger patients (p = 0.016). Toxicity was age-independent except for a higher rate of grade III/IV leukopenia in the elderly (34% vs 21%, p = 0.007). Death on therapy was more frequent (18% vs 11%; p = 0.027), and progression-free survival (PFS) (4.0 vs 7.7 months, p = 0.014) and overall survival (12.5 vs 26.2 months, p0.001) inferior, in the elderly. A striking difference between younger and elderly patients was the PFS of CR patients of 35.0 in the younger vs 16.1 in the elderly patients (p = 0.024). Elderly patients were treated less often and less aggressively at salvage. However, age was not associated with survival from salvage whole brain radiotherapy in patients progressing during primary HD-MTX-based chemotherapy (p = 0.633).Lower response rate and higher mortality on HD-MTX-based chemotherapy as well as lower PFS of CR patients and less salvage therapy contribute to the poor prognosis of elderly patients with PCNSL.

Purpose: Homing of malignant lymphocytes to the central nervous system (CNS) may play a role in the pathogenesis of CNS lymphoma. In this study, we evaluated the chemokines CXCL12 and CXCL13 in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma. Experimental Design: Samples from 30 patients with CNS lymphoma (23 with primary and 7 with secondary CNS lymphoma; all B-cell lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood-brain barrier disruption was estimated by the CSF/serum albumin ratio. Results: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were significantly higher in CNS lymphoma patients as compared with controls (P < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma, CXCL13 concentration in CSF correlated with the degree of blood-brain barrier disruption (R = 0.66; P = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients during therapy decreased in five patients who responded to chemotherapy and increased in two with lymphoma progression. Conclusions: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients, which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies. (Clin Cancer Res 2009;15(19):5968–73)

International audience; RNA quality is critical to achieve valid results in microarray experiments and to save resources. The RNA integrity number (RIN) can be measured with minimal sample consumption by microfluidics-based capillary electrophoresis. To determine whether RIN can predict the qualitative outcome of microarray hybridization, we measured RIN in total RNA samples from 484 different experiments by the 2100 Bioanalyzer system and correlated with the percentage of present calls (%pc) of downstream oligonucleotide microarrays. The correlation coefficient for RNA and %pc in all 408 samples for which the bioanalyzer algorithm was able to produce an RIN was 0.475 (

Most patients with primary CNS lymphoma (PCNSL) relapse after primary therapy. Standard salvage treatment has not yet been established in PCNSL. Anti-CD20 immunotherapy has expanded treatment options in systemic B-cell lymphoma; however, its use is limited by reconstitution of the blood-brain barrier after tumor shrinkage. The aim of this phase II trial was to evaluate the therapeutic efficacy, toxicity, and biodistribution of yttrium-90 ((90)Y) ibritumomab tiuxetan in PCNSL. Ten patients with relapsed PCNSL were included in a phase II trial and treated with the (90)Y-labeled anti-CD20 antibody ibritumomab tiuxetan. Nine patients actually received the planned radioimmunotherapy. In six patients, biodistribution of the antibody was measured by indium-111 ((111)In) ibritumomab tiuxetan whole-body scans and single-photon-emission CT (SPECT) of the brain. All patients were evaluated for toxicity and response at least 4 weeks after therapy. Four patients responded: one patient had a complete response lasting 30+ months, and three patients had short-lived responses of/=4 weeks. Five patients progressed, and one patient did not receive treatment due to an infection prior to (90)Y-antibody administration. Target accumulation of the antibody was demonstrated in four of the six patients examined by SPECT imaging with (111)In ibritumomab tiuxetan. All patients experienced grade 3/4 hematotoxicity but no acute neurotoxicity. Penetration of a therapeutic antibody into PCNSL and significant clinical activity was shown. Because of limited response duration and considerable hematotoxicity, future investigations should focus on a multimodal approach with additional chemotherapy and preferably autologous stem cell support.

In patients with parenchymal brain masses of uncertain origin responsive to corticosteroids, primary CNS lymphoma (PCNSL) should be considered. PCNSL is a rare but aggressive brain tumor that is highly sensitive to high-dose methotrexate (HDMTX)–based chemotherapy. We report a series of six patients with brain masses without histologic confirmation suspicious for PCNSL based on clinical and radiomorphologic criteria after exclusion of some infectious conditions. All patients were treated with HDMTX. We observed two complete responses, two partial responses, and one stable disease. One patient had progressive disease and received rescue whole-brain irradiation. All patients were alive without disease progression 12–48 months after HDMTX start. No symptoms of late neurotoxicity have occurred so far. The response and survival data in this small series of patients are encouraging and suggest a benefit for patients with suspected PCNSL after initial treatment with HDMTX.

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-s 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 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.

Metastatic uveal melanoma has a poor prognosis and limited therapeutic options. Proteoglycans are involved in tumor cell invasion and metastatic behavior. The mAbB5 stains a chondroitin sulphate proteoglycan (CSPG) on cutaneous melanoma cells. Here, we compare the B5-staining of CSPG in primaries and metastases of uveal melanoma.Immunohistopathological staining was performed in 15 cutaneous and 39 uveal melanoma samples. A score for intracellular and surface staining was established. B5 staining was compared in primaries and metastases of uveal melanoma using Student's t-test.Eight of 11 (73%) uveal melanoma metastases were positive for B5-staining whereas only 5 of 28 (18%) primary uveal melanoma samples were B5-positive (P0.001). Nine of 15 cutaneous melanoma samples (60%) were B5-positive without significant difference between primary and metastatic lesions. Surface staining was found both on uveal melanoma metastases and cutaneous melanomas.CSPG was expressed significantly more often in metastases than in primaries of uveal melanoma. It potentially may be one factor associated with metastatic spread. Further studies are needed to determine its use as prognostic factor. The mAbB5 may also be a promising tool for immunotherapy due to its strong staining of CSPG on the surface of cutaneous and metastatic uveal melanoma cells.

OBJECTIVE: To report a case of reversible ageusia in a patient with multiple myeloma receiving pegylated liposomal doxorubicin. CASE SUMMARY: A 67–year-old man with a history of arterial hypertension and persisting left bundle-branch block was diagnosed with multiple myeloma. He was initially treated with cyclophosphamide 200 mg/m2 (days 1–4), pegylated liposomal doxorubicin 20 mg/m2 (day 1), and dexamethasone 40 mg (days 1–4) (CLAD). That treatment was followed by high-dose melphalan therapy and autologous peripheral stem-cell transplantation. The disease recurred 18 months later, and renal failure developed. The patient was again treated with the CLAD protocol. After the first cycle, almost complete ageusia occurred, along with weight loss and severe depression. Chemotherapy was continued, but pegylated liposomal doxorubicin was replaced by conventional doxorubicin. Within 12 weeks, the patient's sense of taste returned to normal. DISCUSSION: Pegylated liposomal anthracyclines are increasingly being used as a less cardiotoxic alternative to conventional doxorubicin in first- and second-line therapy of multiple myeloma. Whereas cardiotoxicity and unspecific reactions are seen less frequently, palmar—plantar erythrodysesthesia is a common reaction to pegylated liposomal anthracyclines. No other reasons for ageusia in our patient could be identified. Based on the Naranjo probability scale, ageusia was rated as a probable reaction to pegylated liposomal doxorubicin. CONCLUSIONS: As with all new and innovative drugs, thorough documentation of infrequent adverse events is necessary. We would like to raise awareness for ageusia, which appears to be a rare but severely impairing adverse reaction to a relatively new pharmacologic agent.

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.