ALBERT

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: The Pool cryoprecipitate provides an effective source of the factor lacking in the plasma of patients with von Willebrand’s disease which is necessary for a normal bleeding time. Correction of the bleeding time appears to be necessary for control of bleeding in some instances of severe spontaneous hemorrhage. None of the commercially prepared antihemophilic factor concentrates prepared in this country contain adequate amounts of the extremely labile bleeding time factor.

Description: Sera obtained from one hundred patients before and after open heart surgery and concomitant transfusion were tested for anti-γ globulin, antileukocyte, and antiplatelet antibodies. The sera of 34 patients contained anti-γ globulin antibodies of one or another variety for the first time after the operation. Of eight additional patients who were seropositive before the operation, seven developed anti-γ globulin antibodies of different specificity postoperatively. Gm-specific antibodies were detected after the operation in 14 patients, Gm antibodies of unknown specificity in nine, and anti-antibodies in 18. The anti-antibodies were of the Andressen type in 17 cases and of the Milgrom type in one. Leukoagglutinins were detected postoperatively in 33 patients, and platelet antibodies in three. Possible explanations for the high incidence of anti-γ globulin antibodies found in this study include (1) the transfusion of many units of blood during a single surgical procedure, (2) an increase in the antigenicity of the gamma globulins due to aggregation or to changes in molecular configuration during extracorporeal circulation, and (3) an optimal interval between antigenic stimulation and collection of blood for testing.

Description: A variety of technics for assay of fibrinogen were investigated. Greatest accuracy was obtained with a slightly modified Ratnoff-Menzie procedure. One hundred presumably normal blood donors had an average fibrinogen level of 225 mg. per 100 ml. of plasma, with a range from 147 to 319 mg. The levels were not appreciably influenced by age, sex or "reactions" to donation of blood. Using this assay, over-all fibrinolytic activity was estimated by duplicate assays employing 4-hour incubation of the diluted clot, lysis being inhibited in one of the tubes by epsilon amino caproic acid. The technic showed significant degrees of fibrinolytic activity in the plasma of most patients after open heart surgery as compared with the normal controls.

Description: Background: Cobomarsen (MRG-106) is an inhibitor of miR-155, a microRNA with a strong link to cutaneous T cell lymphoma (CTCL) pathogenesis. The goals of this first in human study are to evaluate the safety, tolerability, pharmacokinetics, and efficacy of cobomarsen in mycosis fungoides (MF) patients. Methods: This Phase 1 trial evaluated cobomarsen given via intralesional injection (75 mg/dose), subcutaneous (SC), IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Patients must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Patients received 6 doses, either subcutaneous or intravenous, in the first 26 days of the study followed by weekly or bi-monthly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of cobomarsen on quality of life was assessed by Skindex-29. Results: 38 subjects receiving IV or SC treatment (25 male/13 female, median age 59 years) have been on study for up to 22 months. As of the data cut off, no serious AEs have been attributed to cobomarsen. The most common AEs reported in greater than 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed dose limiting toxicities (DLTs): Grade 3 worsening pruritus and Grade 3 tumor flare. The maximum tolerated dose (MTD) has not yet been reached. In the subcutaneous and IV cohorts, 29 out of 32 (91%) evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). The best improvements were observed after more than 1 month of treatment. Eleven out of twenty-one (52%) patients receiving more than one month of dosing (6 doses) achieved greater than 50% reduction in mSWAT score. The mean duration of response (n=11) was 213 days, as of data cut off. Eight patients achieved a partial response meeting the criteria for ORR4, an objective response rate lasting at least four months in duration. The overall skin response in patients who received cobomarsen as monotherapy or cobomarsen with concurrent stable therapy were not significantly different. Improvement in quality of life (QOL), as measured by the Skindex-29 total score, correlated with reductions in mSWAT score during the treatment phase. Conclusions: These results demonstrate that cobomarsen is well-tolerated, has clinical activity, and has the potential to impact MF quality of life. These encouraging data support the continued investigation of cobomarsen in the CTCL population. The study is expanded to enroll patients with other hematologic malignancies in which miR-155 is elevated and relevant, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and adult T cell lymphoma/leukemia (ATLL). Final safety and efficacy data on CTCL mycosis fungoides will be presented. Disclosures Foss: Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Mallinkrodt: Consultancy.

Description: Background Both primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement carry a poor prognosis. While there has been interest in intensification of treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT), the side effect profile and long-term efficacy of consolidative transplant are not yet clear. Our aim was to investigate the efficacy and safety of a conditioning regimen of thiotepa, busulfan, and cyclophosphamide (TBC) (Soussain C., et al, J. Clin. Oncol., 19:742-749, 2001) followed by ASCT in patients with PCNSL or NHL with CNS involvement. Methods A retrospective analysis was performed among consecutive patients undergoing consolidative ASCT with TBC conditioning for PCNSL or NHL with CNS involvement between July 2006 and December 2017. For patients with PCNSL, a uniform induction therapy was given that consisted of rituximab and high dose methotrexate for 2-4 cycles followed by rituximab / cytarabine / thiotepa for 1-2 cycles based on published data (Illerhaus et al, Blood 120, no. 21 (2012): 302). For patients with secondary CNS lymphoma or relapsed disease, a variety of chemotherapy regimens were used at the discretion of the treating physician. Progression-free survival (PFS) was defined from the date of transplant to the date of relapse or any cause of death. Overall survival (OS) was calculated from the date of transplant to death. Results Forty-eight patients with NHL who underwent ASCT with TBC conditioning were identified: 27 patients with PCNSL, 12 patients with secondary CNSL, and 9 patients with relapsed disease with CNS involvement. Twenty-nine patients (60%) were in their first complete response (CR1) at the time of transplant. The median time from diagnosis to transplant was 7.1 months (range 3.7- 144.4). The median follow-up time after transplant was 23.9 months (range 8.6 - 59.6 months). The median time to neutrophil recovery (absolute neutrophil count 〉 500/uL) and platelet recovery (〉20,000 x 103/μL for 〉 2 consecutive days) were 9 days (range 7-12 days) and 7 days (range 1-40 days), respectively. Four patients were noted to have anemia (hemoglobin decrease 〉2 g/dL from baseline). Most patients (89.5%) experienced febrile neutropenia and 68.6% were found to have infection. Other common side effects included mucositis (89.5%, 35.4% with grade 3 or higher), electrolyte abnormalities (89.5%), dermatologic sequelae (31.3%), reversible neurotoxicity (18.8%), renal injury (16.7%), and hemorrhagic cystitis (8.3%). Four patients (8.3%) experienced treatment-related mortality, 3 of which had secondary CNSL. No evidence of pulmonary toxicity or veno-occlusive disease was noted. The 1-year PFS was 78% (95% CI 63.3%-88.0%), and 1-year OS was 80.5% (95% CI 66%-89.8%). When analyzed according to primary diagnosis, 1-year PFS was 82.6% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.69). According to diagnosis, 1-year OS was 87% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.47). Univariate analysis was performed to analyze gender, ethnicity, age 〉 60, Karnofsky score ≥ 80, diagnosis, cell of origin, and transplant in CR1 versus CR2 or partial response as independent predictors of PFS and OS. Only age (p = 0.001, 95% CI 1.9-42.6 for PFS; p = 0.030, 95% CI 0.99-23.42 for OS) and Karnofsky score ≥ 80 (p = 0.017, 95% CI 0.07-0.81 for PFS; p = 0.047, 95% CI 0.06-1.03 for OS) were found to be significant. Conclusion High dose chemotherapy and autologous stem cell transplant using TBC conditioning for PCNSL and secondary CNSL appears to have encouraging long term efficacy with manageable side effects. Future studies looking at longer follow-up periods and comparison with other conditioning regimens is warranted. Disclosures Schiller: Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding.

Description: VEGFR-3 is a transmembrane receptor tyrosine kinase that is activated by its ligands VEGF-C and VEGF-D. Although VEGFR-3 has been linked primarily to the regulation of lymphangiogenesis, in the present study, we demonstrate a role for VEGFR-3 in megakaryopoiesis. Using a human erythroleukemia cell line and primary murine BM cells, we show that VEGFR-3 is expressed on megakaryocytic progenitor cells through to the promegakaryoblast stage. Functionally, specific activation of VEGFR-3 impaired the transition to polyploidy of CD41+ cells in primary BM cultures. Blockade of VEGFR-3 promoted endoreplication consistently. In vivo, long-term activation or blockade of VEGFR-3 did not affect steady-state murine megakaryopoiesis or platelet counts significantly. However, activation of VEGFR-3 in sublethally irradiated mice resulted in significantly elevated numbers of CD41+ cells in the BM and a significant increase in diploid CD41+ cells, whereas the number of polyploid CD41+ cells was reduced significantly. Moreover, activation of VEGFR-3 increased platelet counts in thrombopoietin-treated mice significantly and modulated 5-fluorouracil–induced thrombocytosis strongly, suggesting a regulatory role for VEGFR-3 in megakaryopoiesis.