ALBERT

Description: Key Points Pathogen-inactivated platelets were noninferior in preventing bleeding only in intention-to-treat analysis. In contrast to animal models, alloimmunization could not be prevented when using pathogen-inactivated platelets.

Description: The t(15;17) translocation in acute promyelocytic leukemia (APL) yields a PML/RAR-α fusion messenger RNA species that can be detected by reverse transcription–polymerase chain reaction (RT-PCR) amplification. Breakpoints within intron 3 of PML produce a short PML/RAR-α isoform, whereas breakpoints within intron 6 result in a longer form. Using RT-PCR, serial evaluations were performed on the bone marrow of 82 patients with APL (median follow-up, 〉 63 months) who received retinoic acid (RA) induction followed by postremission treatment with chemotherapy, RA, and biologic agents. Sixty-four patients attained a clinical complete remission and had at least 2 RT-PCR assays performed after completing therapy. Forty of 47 patients (85%) with newly diagnosed APL who were induced using RA had residual disease detectable by RT-PCR before additional therapy. After 3 cycles of consolidation therapy, residual disease was found in only 4 of 40 evaluable patients (10%). Among newly diagnosed patients who had 2 or more negative RT-PCR assays, only 3 of 41 (7%) had a relapse, whereas all 4 patients (100%) who had 2 or more positive results had a relapse. Among 63 newly diagnosed patients, those who expressed the short isoform appeared to have shorter disease-free and overall survival durations than patients who expressed the long isoform. These data indicate that 2 or more negative RT-PCR assays on bone marrow, performed at least 1 month apart after completing therapy, are strongly associated with long-term remissions. Conversely, a confirmed positive test is highly predictive of relapse.

Description: Background: CXCR4 is a chemokine receptor overexpressed in more than 20 tumor types, including malignant plasma cells. The CXCR4/CXCL12 (SDF-1) axis has been known for many years as a critical regulator of tumor proliferation, cell, as well as migration into and out of the bone marrow. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal anti-CXCR4 antibody which inhibits the binding of CXCR4 to CXCL12. This study aimed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of Ulocuplumab alone and in combination with lenalidomide plus dexamethasone (Len-Dex), or in combination with bortezomib plus dexamethasone (Bor-Dex) in subjects with relapsed/refractory multiple myeloma. Patients / Methods: Patients were eligible for this trial if they were 18 years of age or older with relapsed or relapsed/refractory multiple myeloma after having received at least 2 prior lines of treatment. Patients in whom who both lenalidomide and bortezomib had failed were not excluded from re-treatment with the same regimen. Patients were enrolled at four cancer centers in the U.S. from October 2011 to March 2014. Ulocuplumab (1, 3 and 10 mg/kg) was dose escalated with a 3-plus-3 design with doses of Len-Dex or Bor-Dex to identify maximum tolerated dose (MTD). Ulocuplumab was given weekly in combination with either 25mg lenalidomide on days 1-21 and 40mg oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycles on Arm A or 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 and 20mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day cycles on Arm B since cycle 2. The primary endpoints for this study were dose-limiting toxicities. Other key safety endpoints included incidence of adverse events (AE), AEs leading to discontinuation, SAEs, deaths, and laboratory abnormalities. The efficacy endpoints included overall responses, duration of response, and time to response. Responses were assessed using the IMWG criteria. Results: Forty-six patients were enrolled (median age, 60 years; range, 53-67). The median number of prior therapies was 3 (range, 1-11), with 70.0% of patients having received ≥ 3 lines of treatment. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events of any grade were neutropenia (13 patients, 43.3%), diarrhea (10 patients, 33.3%), thrombocytopenia (10 patients, 33.3%), and fatigue (7 patients, 23.3%) in Arm A; and thrombocytopenia (6 patients, 37.5%), fatigue (4 patients, 25.0%) and anemia (4 patients, 25.0%) in Arm B. The overall response rate (≥ partial response) for all subjects in escalation and expansion was 44.4% (20/45). The median time to response was 1.5 months (range 0.4-7.8 months) for Arm A and 1.0 month (range 0.5-3.7 months) for Arm B, respectively. Of note, the combination of Ulocuplumab with Len-Dex showed a high response rate of 55.2% and a clinical benefit rate ( ≥ minimal response) of 72.4%, including patients who have been previously treated with lenalidomide. Conclusion: This study shows that the blockade of the CXCR4-CXCL12 axis by Ulocuplumab is safe and has an encouraging response rate of over 50% in the Len-Dex arm of patients with relapsed/refractory myeloma. The distinct mechanisms of action of this antibody, as well as its non- cross resistance with currently approved approaches, make it a new class of anti-myeloma drug that warrants further exploration and evaluation in future clinical trials. Disclosures Ghobrial: Takeda: Consultancy; Celgene: Consultancy; BMS: Consultancy; Janssen: Consultancy. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Consultancy; Takeda Millennium: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership; C4 Therapeutics: Equity Ownership. Becker:GlycoMimetics: Research Funding.

Description: Arsenic trioxide (As2O3) has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As2O3 exerts its antileukemic effect remains uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these observations, we hypothesized that As2O3 may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentrations of As2O3results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As2O3 caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As2O3 prevented capillary tubule and branch formation in an in vitro endothelial cell–differentiation assay. In conclusion, we believe that As2O3 interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production.

Description: Background: Across sub-Saharan Africa, blood supplies are threatened by numerous pathogens. In some locations, Plasmodium parasitemia prevalence in donor blood is nearly 50%. Donor testing for malaria in these areas is not effective and the risk of transfusion-transmitted malaria (TTM) is high. The Mirasol® PRT System for Whole Blood (WB) is a medical device intended for extracorporeal pathogen reduction of WB. The current clinical study evaluated the ability of Mirasol-treated WB to reduce the incidence of TTM. Study Design/Methods: This was a prospective, randomized, double-blind, controlled, single-center study in Ghana, which is hyperendemic for malaria. The study had 90% power to demonstrate a 90% reduction in TTM. Hospitalized patients requiring WB transfusions were randomly allocated to receive ≤ 2 transfusions of standard (untreated) or Mirasol-treated WB. The primary endpoint was the incidence of TTM as measured by quantitative polymerase chain reaction and Plasmodium alleleic sequence homology between transfused and patient WB during 28 days of follow-up. Patient safety was assessed by monitoring treatment-emergent adverse events (TEAEs) and transfusion reactions.Clinical outcomes related to hemoglobin increments, hemostatic parameters, and clinical chemistries were monitored for 28 days post-transfusion. Results: Overall, 226 subjects (113 Mirasol, 113 Untreated) were enrolled; 223 subjects were included in the safety analysis. Sixty-five (65) subjects were non-parasitemic at pre-transfusion (28 Mirasol, 37 Untreated) and received at least 1 parasitemic WB transfusion. Of 16 cases of suspected TTM (3 Mirasol, 13 Untreated) with 2 consecutive days of parasitemia, 9 were confirmed by alleleic homology (1 Mirasol, 8 Untreated). Incidence of TTM was significantly reduced in patients receiving treated products. Hemoglobin (mean [standard deviation]) was similar between groups at baseline (6.71 g/dL; p = 1.0), and Day 1 following 1 transfusion (8.53 [2.0] vs 8.49 [1.5] g/dL; p = 0.93) or 2 transfusions (7.09 [1.5] vs 7.38 [1.6] g/dL; p = 0.33). Ninety-two subjects (48 Mirasol, 44 Untreated) reported 145 TEAEs (75 Mirasol, 70 Untreated). Transfusion reactions were observed in 8.1% and 13.4% of subjects receiving Mirasol-treated and untreated WB, respectively. Table. Incidence of TTM Mirasol n (%); 95% CI Untreated n (%); 95% CI P-Value 2 Consecutive days of ParasitemiaN = 65 3 (10.7); 2.3, 28.2 n = 28 13 (35.1); 20.2, 52.2n = 37 〈 0.05 2 Consecutive days of Parasitemia and 〉2 Allele match by PCRN = 65 1 (3.6); 0.1, 18.3n = 28 8 (21.6); 9.8, 38.2n = 37 〈 0.05 ITT PopulationN = 223 1 (0.9); 0.0, 4.9n = 111 8 (7.1); 3.1, 13.6n = 112 〈 0.05 Abbreviation: CI = confidence interval, ITT = intent-to-treat, PCR = polymerase chain reaction. Conclusions: The primary endpoint of the study was met. Mirasol treatment of WB clinically and statistically reduced TTM infections in the study population. This was the first human clinical study demonstrating that a PRT system can reduce transmission of a bloodborne pathogen. No safety issues were related to the device or device-treated WB. Transfusion reactions did not differ between patients receiving Mirasol-treated or untreated WB. Hemoglobin increments and transfusion outcome parameters in transfused patients did not differ between the treatment groups. Disclosures Allain: Terumo BCT: Consultancy. Owusu-Ofori:Terumo BCT: Other: Clinical Study Sub-Investigator. Marschner:Terumo BCT: Employment. Goodrich:Terumo BCT: Employment. Owusu-Ofori:Terumo BCT: Other: Clinical Study Investigator.

Description: Arsenic trioxide (As2O3) has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As2O3 exerts its antileukemic effect remains uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these observations, we hypothesized that As2O3 may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentrations of As2O3results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As2O3 caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As2O3 prevented capillary tubule and branch formation in an in vitro endothelial cell–differentiation assay. In conclusion, we believe that As2O3 interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production.

Description: This study identified missense mutations in the ligand binding domain of the oncoprotein PML-RARα in 5 of 8 patients with acute promyelocytic leukemia (APL) with 2 or more relapses and 2 or more previous courses of all-trans retinoic acid (RA)–containing therapy. Four mutations were novel (Lys207Asn, Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had been previously identified (Arg272Gln; normal RARα1 codon assignment). Five patients were treated with repeat RA plus phenylbutyrate (PB), a histone deacetylase inhibitor, and one patient experienced a prolonged clinical remission. Of the 5 RA + PB-treated patients, 4 had PML-RARα mutations. The Gly289Arg mutation in the clinical responder produced the most defective PML-RARα function in the presence of RA with or without sodium butyrate (NaB) or trichostatin A. Relapse APL cells from this patient failed to differentiate in response to RA but partially differentiated in response to NaB alone, which was augmented by RA. In contrast, NaB alone had no differentiation effect on APL cells from another mutant case (Pro407Ser) but enhanced differentiation induced by RA. These results indicate that PML-RARα mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RARα was not correlated with clinical response to RA + PB treatment, and suggest that the response to RA + PB therapy in one patient was related to the ability of PB to circumvent the blocked RA-regulated gene response pathway.