GSK1120212, a MEK1/MEK2 Inhibitor, Demonstrates Acceptable Tolerability and Preliminary Activity In a Dose Rising Trial In Subjects with AML and Other Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3281-3281 ◽  
Author(s):  
Gautam Borthakur ◽  
James M. Foran ◽  
Tapan Kadia ◽  
Elias Jabbour ◽  
Paul Wissel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Cell Lines ◽  
Research Funding ◽  
Loading Dose ◽  
Bone Marrow Blast ◽  
Blast Count ◽  
Visual Changes ◽  
Refractory Aml

Abstract Abstract 3281 Background: MEK (mitogen-activated extracellular signal-related kinase) is downstream of the RAS/RAF pathway and is activated by many upstream oncogenic drivers. GSK1120212 is a potent and selective allosteric inhibitor of MEK 1 and 2 kinases. In vitro, GSK1120212 inhibited proliferation of myeloid cell lines selectively as compared to lymphoid cell lines. This 2 part study of a single daily oral dosing regimen was conducted to define the recommended Phase 2 dose, evaluate pharmacokinetics, and assess preliminary activity in patients with relapsed or refractory AML, MDS, ALL or CMML. Methods: Subjects with WBC< 30,000/uL who met hepatic, renal and cardiac function criteria were eligible for participation. GSK1120212 was given orally, once daily in the following dose cohorts: 3mg loading dose followed by 1mg/day (n=3), 1mg/day without loading dose (n=1), and 2mg/day without loading dose (n=9). The loading dose was discontinued after cohort 1, based on findings in the phase I solid tumor study (J Clin Oncol 28:15s, 2010 (suppl, abstr 2503). Results: Fourteen subjects (10 with AML, 2 MDS transformed to AML, 1 MDS, 1 ALL) entered the trial. Eight were male, and median age was 65 years (range 33 to 85). Pharmacokinetic analysis showed that, upon repeat dosing, GSK1120212 exposure increased in a dose-proportional manner, had a small peak:trough ratio of approximately 4 and an effective half-life of approximately 7.7 days. Steady state concentrations were reached by day 15. Both single and repeat dose pharmacokinetics of GSK1120212 appeared to be similar to a phase I study in patients with solid tumors. Systemic exposure exceeded concentrations that inhibited in vitro leukemic cell proliferation. At the 2mg/day dose level (n=9), drug-related adverse events were diarrhea (7 overall; 6-Grade 1/2, 1-Grade 3), rash (3-Grade 1/2), fatigue (4-Grade 1/2), visual changes (3 Grade 1/2). One subject experienced a Grade 2 reversible serous retinopathy associated visual changes which resolved after drug discontinuation. One dose limiting toxicity was seen in a subject with disease-related Grade 4 thrombocytopenia and pneumonia who experienced a Grade 5 cerebrovascular accident possibly related to drug. One subject in the 2mg/day cohort achieved a CR; peripheral blast count was reduced from 30% at baseline to 0% and bone marrow blast count was reduced from 50% at baseline to 3%. During this time, platelet count increased from 48K to a maximum of 276K. Initial salutary effect was seen after 2 weeks on therapy and duration of CR was 4 weeks bone marrow blast count was 3% and 5%, respectively, at the beginning and end of the 4 week CR duration. Conclusion: GSK1120212 administered at 2mg/day orally was tolerable in subjects with relapsed or refractory AML and other leukemias. This dose regimen achieved plasma concentrations sufficient for target inhibition and showed preliminary anti-leukemic clinical activity. Based on these results, a phase II study in AML, MDS and CMML has been initiated. Disclosures: Borthakur: GlaxoSmithKline: Research Funding. Foran:GlaxoSmithKline: Research Funding. Kadia:GlaxoSmithKline: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Wissel:GlaxoSmithKline: Employment. Cox:GlaxoSmithKline: Employment. Xu:GlaxoSmithKline: Employment. Bauman:GlaxoSmithKline: Employment. Baccus:GlaxoSmithKline: Research Funding. Connor:GlaxoSmithKline: Research Funding. Cortes:GlaxoSmithKline: Research Funding. Kantarjian:GlaxoSmithKline: Research Funding.

Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2984-2984 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen Ritchie ◽  
Alan F. List ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Molar Ratio ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (&gt;60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

Silencing The Sialyltransferase Gene ST3GAL6 Inhibits Adhesion and Migration Of Myeloma Cells In Vitro and Reduces The Homing and Proliferation Of Tumor Cells In Vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 275-275
Author(s):  
Siobhan Glavey ◽  
Salomon Manier ◽  
Antonio Sacco ◽  
Michaela R Reagan ◽  
Yuji Mishima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Research Funding ◽  
Advisory Board ◽  
Myeloma Cells ◽  
Sialyl Lewis ◽  
And Migration ◽  
Rpmi 8226

Abstract Background Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The adhesion and trafficking of multiple myeloma (MM) cells is strongly influenced by glycosylation and multiple myeloma cells express a variety of adhesion molecules, including selectin ligands and integrins, which are typically dependent on glycosylation for their function. We have previously reported that the sialyltransferase ST3GAL6 is up-regulated in plasma cells from MM patients and that increased expression is associated with inferior overall survival (OS) in MM gene expression profiling (GEP) datasets. The functional significance of increased sialylation of MM cells has not previously been reported. Methods MM cell lines MM1s and RPMI-8226 were confirmed to have high expression levels of ST3GAL6 at the gene and protein level compared to healthy controls. Knockdown of ST3GAL6 was confirmed in MM cell lines RPMI-8226 and MM1s using lentiviral shRNAs targeting different regions in the ST3GAL6 mRNA. Specific ST3GAL6 knockdown was confirmed by reduced ST3GAL6 mRNA and protein expression in comparison to a scrambled control. In a calcein-AM fluorescence based adhesion assay we next evaluated the effects of ST3GAL6 knockdown on MM-cell adhesion to bone marrow stromal cells (BMSC’s) and fibronectin coated plates. Migration to 30nM SDF1-α was assessed using transwell plates comparing ST3GAL6 knockdown cells to scrambled controls. The commercially available sialyltransferase inhibitor 3Fax-Neu5Ac was used to pre-treat MM cells in vitro prior to assessment of apoptosis by flow cytometry. shST3GAL6 MM1s cells positive for green fluorescent protein and luciferin (GFP-Luc+) were injected into tail veins of SCID-Bg mice (5x106 cells, n=5/group) and mice were followed weekly using bioluminescent imaging (BLI) for tumor development. Bone marrow homing of tumor cells was assessed using in vivoconfocal imaging of the skull vasculature (n=3/group). Results Knockdown of ST3GAL6 in MM cell lines resulted in a 50% reduction in cell surface staining with the monoclonal antibody HECA-452. This indicated reduced expression of cutaneous lymphocyte associated antigen (CLA), a carbohydrate domain shared by sialyl Lewis X (sLex) and sialyl Lewis a (sLea) antigens, confirming suppression of ST3GAL6 activity. There was a significant reduction in the ability of knockdown cells to adhere to BMSC’s and fibronectin in-vitro compared to scrambled controls (P=0.016, 0.032 respectively). Migration ability of these cells in response to SDF1-α was also reduced (P=0.01). In vivo in a xenograft SCID-Bg mouse model shST3GAL6 cells demonstrated a reduced tumor burden as assessed by weekly BLI (P=0.017 at week 4). A consolidated map of the skull bone marrow niche in mice injected with shST3GAL6 MM1s GFP-Luc+ cells revealed a reduced homing ability of these cells in comparison to mice injected with scrambled control cells. Treatment of the MM cell lines MM1s and RPMI-8226 with a sialyltransferase inhibitor 3Fax-Neu5Ac resulted in almost complete elimination of cell surface sLex and/or sLea expression as determined by HECA-452 staining. Following pre-treatment with 3Fax-Neu5Ac, MM1S cells grown in co-culture with BMSC’s cells showed increased sensitivity to Bortezomib compared to cells treated with bortezomib alone. Conclusions shRNA knockdown of ST3GAL6 in MM cells significantly inhibits adhesion and migration in vitro with reduced homing and proliferation potential in vivo. In conjunction with the results of enzymatic inhibition this indicates that sialylation may play an important role in the malignant behavior of MM cells. Studies are ongoing to address the potential role of altered glycosylation in MM. Disclosures: Ghobrial: Onyx: Advisoryboard Other; BMS: Advisory board, Advisory board Other, Research Funding; Noxxon: Research Funding; Sanofi: Research Funding.

scholarly journals Thioguanine Combined with Decitabine Can Overcome Resistance to Hypomethylating Agents: Final Results of a Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/Decitabine Combination in Patients with Advanced Myeloid Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2816-2816
Author(s):  
Daniel J. Lee ◽  
Todd L. Rosenblat ◽  
Mark Lawrence Heaney ◽  
Joseph G. Jurcic ◽  
Azra Raza ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Hypomethylating Agents ◽  
Screening Assay ◽  
Chemosensitivity Assay ◽  
Induction Cycle ◽  
Refractory Aml

Abstract Background: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that combination treatment with thioguanine and decitabine can restore therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. To test the safety and synergistic efficacy of this combination in patients with advanced myeloid malignancies, we performed a Phase I dose-escalation trial of thioguanine given with decitabine. Patients and Methods: Patients with untreated AML ≥60 years of age and ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. The primary objective was to determine the maximum tolerated dose (MTD) of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Patient-specific pharmacodynamic measures to assess the biologic activity of thioguanine-decitabine were also performed. These included an in vitro chemosensitivity assay, BH3 profiling to measure the degree to which the leukemic blasts were primed for apoptosis, and genome-wide analysis of DNA methylation changes. Results: Twelve patients (median age 67; range 56-83) with de novo AML (n=1), secondary AML (n=6), relapsed/refractory AML (n=4), and chronic myelomonocytic leukemia (CMML) (n=1) were treated. Three patients experienced dose-limiting toxicity (DLT), which were acute renal failure requiring hemodialysis (80 mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120 mg/m2), and grade 4 sepsis preventing continued treatment (120 mg/m2). Thioguanine at 80 mg/m2 was determined to be the MTD. Eleven of the 12 patients completed the first induction cycle, and 6 patients completed a second, identical induction cycle. The median number of cycles administered was 3 (range 1-8). One patient experienced a DLT prior to the first response assessment and was removed from study. The ORR in this intent-to-treat study was 67% (8/12). Six patients achieved a CR or CRi, one obtained a morphologic leukemia-free state, and one patient had a PR. Responses were observed in all disease types. Five of the 8 responses, including 4 CR/CRi, were achieved with thioguanine at 80 mg/m2, suggesting no loss of efficacy at the MTD compared with the higher dose level. All 11 evaluable patients had ≥50% reduction in bone marrow blast percentages after induction therapy. Six patients had previously received single-agent hypomethylating therapy, and 5 (83%) of these patients responded, demonstrating that thioguanine-decitabine can rescue prior hypomethylating agent failure. Out of the 8 responders, four (50%) proceeded to allogeneic stem cell transplantation (SCT), two relapsed after CR or CRi, one had a CNS-only relapse after achieving a CR, and one patient experienced DLT and was removed from the study. Of the four patients who proceeded to allogeneic SCT, two patients died in CR from transplant-related toxicity, one relapsed, and one patient remains alive and in remission greater than 2 years. Median PFS in responding patients was 42 weeks (range, 10-not reached, weeks). In vitro pharmacodynamic studies currently have been completed on samples from the first 6 patients treated on this trial. The chemosensitivity assay results on pre-treatment mononuclear cells directly correlated with initial response. In addition, significant apoptotic priming of the blasts, as suggested from BH3 profiling, also corresponded to initial clinical response. Conclusions: Thioguanine-decitabine can be administered safely and induce remission, even among patients who had previously been treated with hypomethylating agents. Intriguingly, preliminary results from the chemosensitivity screening assay and BH3 profiling correlated well with clinical responses. Additional correlative studies including DNA methylation analysis are ongoing to better understand the mechanism of synergy between thioguanine and decitabine. A multi-center Phase II trial is planned. Disclosures Jurcic: Astellas: Research Funding. Letai:Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

scholarly journals TBK1/Ikkε Inhibitor Amlx Blocks Multiple Myeloma Cell Growth in Vitro and In Vivo

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4504-4504
Author(s):  
Quanhong Sun ◽  
Peng Zhang ◽  
Juraj Adamik ◽  
Konstantinos Lontos ◽  
Valentina Marchica ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Cell Lines ◽  
Bone Disease ◽  
Research Funding ◽  
Ex Vivo ◽  
Dominant Negative ◽  
Induction Of Apoptosis

Abstract Multiple myeloma (MM) is the most frequent cancer to involve the skeleton and remains incurable for most patients, thus novel therapies are needed. MM bone disease is characterized by osteolytic lesions that contribute significantly to patient morbidity and mortality. We showed that TBK1 signaling is a novel pathway that increases osteoclast (OCL) formation in Paget's disease, an inflammatory bone disease. Therefore, we hypothesized that TBK1 plays a similar role in MM induction of OCL. We found that MM conditioned media (MM-CM) dose-dependently increased bone marrow monocyte (BMM) expression of activated TBK1 protein and enhanced RANKL-driven OCL formation. TBK1 knockdown by shRNA transduction into BMM significantly attenuated the ability of MM-CM to increase OCL differentiation without altering OCL differentiation in control media. We found that the TBK1/IKKε inhibitor Amlexanox (Amlx) blocked normal and MM-enhanced OCL formation. Importantly, TBK1 mRNA expression in CD138+ plasma cells (PC) isolated from MM or PC leukemia patients is significantly higher as compared to PC from Monoclonal Gammopathy of Undetermined Significance (MGUS) patients. Therefore, we tested whether targeting the TBK1/ IKKε signaling pathways would also affect MM cells. We found that Amlx strongly decreased the viability of several MM cell lines and primary MM cells via induction of apoptosis. Amlx treatment of MM cell lines also induced a G1/S blockade, decreased activated ERK1/2, and increased translation of the dominant-negative C/EBPb-LIP isoform in several MM cell lines. The positive-acting C/EBPb-LAP isoform was previously shown to be a critical transcription factor for MM viability. Importantly, Amlx also enhanced the effectiveness of the proteasome inhibitors bortezomib and carfilzomib to kill MM cells in culture. Further, Amlx sensitized MM1.S cells to the induction of apoptosis by the autophagic inhibitor Bafilomycin A. Amlx dose-dependently inhibited tumor growth in a syngeneic MM mouse model in which 5TGM1 MM cells expressing secreted GLuc were injected subcutaneously into immunocompetent C57Bl/KaLwRij. Tumor growth was assessed by measuring tumor volumes and by the levels of secreted GLuc in the blood. Further, OCL formation ex vivo from bone marrow monocytes obtained from AMLX-treated mice versus controls was decreased. Amlx did not affect the viability of primary BMM, bone marrow stromal cells (BMSC), or splenocytes. Further, Amlx treatment of primary BMSC from MM patients or normal donors decreased expression of TNFα, IL-6 and RANKL, thereby decreasing BMSC support of MM survival and OCL differentiation. Amlx pretreatment of BMSC and murine pre-osteoblast MC4 cells also decreased VCAM1 expression and reduced MM cell adhesion, another mechanism for Amlx reduction of bone microenvironmental MM support. These data suggest that targeting TBK1/IKKε signaling may decrease MM bone disease by slowing MM growth, directly and indirectly, and preventing MM-induced osteolysis. Disclosures Giuliani: Janssen Pharmaceutica: Other: Avisory Board, Research Funding; Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding. Roodman:Amgen Denosumab: Membership on an entity's Board of Directors or advisory committees.

Effect of Complete Remission Achievement on Survival In Acute Myeloid Leukemia of the Elderly.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1048-1048
Author(s):  
Felicetto Ferrara ◽  
Cira Riccardi ◽  
Salvatore Palmieri ◽  
Tiziana Izzo ◽  
Antonella Carbone
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Loading Dose ◽  
Refractory Disease ◽  
Bone Marrow Blast ◽  
Blast Count ◽  
Acute Myeloid

Abstract Abstract 1048 The achievement of complete remission (CR) is considered an essential prerequisite for cure in acute myeloid leukemia (AML). Notwithstanding, in older AML patients recent data suggest that, at least for patients receiving new compounds such as hypomethilating agents Azacytidine and Decitabine, the benefit on survival can be independent from CR achievement, namely in patients with low bone marrow blast count (< 30%) at diagnosis. In this study we evaluated the impact of CR achievement on overall survival from a series of 140 patients aged over 60 years; all patients received a therapeutic program including continuous infusion of fludarabine (F) and cytarabine (ARA-C) as induction and consolidation, followed whenever possible by autologous stem cell transplantation (Ferrara et al, Haematologica, 2005). Briefly, F was administered at a loading dose of 10 mg/m2 over 15 min at day 0 followed 6 hours and half later by continuous infusion (c.i.) of 20 mg/m2/24 hours for 72 hours (days 0–2); ARA-C was given at a loading dose of 390 mg/m2 three hours and half after F and then as c.i. over 96 hours at 1440 mg/m2/24 hours (days 0–3). G-CSF was added at day +15 at a dose of 5 μg/kg. A second identical course was planned for patients obtaining partial response, defined as less than 5% blasts in peripheral blood and less than 30% of blasts in the bone marrow. Patients achieving CR, established as less than 5% blasts in the bone marrow, normal blood count and differential and absence of extramedullary leukemia, were programmed to receive an additional identical course as consolidation, reduced of one day (i.e. two days c.i. of F and three days c.i, of ARA-C). The effect of CR was separately analyzed according to karyotype, bone marrow blast count and, in patients with normal karyotype, NPM1 and FLT3 positivity. Of note, patients dead in induction were excluded from survival benefit evaluation. The median age was 69 years (range 61–82). Cytogenetic analysis was successfully in 134/140 patients (96%). Among these 89 (66%) were found as having normal karyotype (NK) and 45 (34%) with different chromosomal abnormalities, mostly complex or involving chromosomes 5 and/or 7, classified as unfavorable (UK). Overall 94 patients (67%) achieved CR; the CR rate was 77 % in NK and 47% in unfavorable karyotype (p:<0.001). Of note, rates of either death in induction (22% vs 14%) or primary refractory disease (33 % vs 8%) were significantly higher in patients with adverse cytogenetics. The median survival for the whole patient population was 10 months; survival was significantly influenced by cytogenetics at diagnosis (12 months for NK vs 7 months for UK), p:<0.001). The median duration of CR was 11 months (16 months for patients with NK as opposed to 7 months for those with UK). The overall impact of CR achievement on survival was remarkable and remained statistically significant after exclusion of patients dead in induction (18 months vs. 6 months, p:< 0.001). The advantage of achieving CR was found in patients with NK, independently from molecular assessment at diagnosis, i.e. NPM1+/FLT3-, NPM1-FLT3-, NPM-FLT3+, NPM+/FLT3+). Of interest, no difference was found as bone marrow blast count at diagnosis, i.e. more or less than 30 %, was concerned in the rate of CR achievement, CR duration and impact of CR on survival either in univariate or multivariate analysis. By separately analyzing patients with UK, the advantage of CR achievement was found only when patients dead in induction were excluded and was limited to 4 months (11 months for remitters vs. 7 months for refractory patients, p:0.04). We conclude that older AML patients with unfavorable karyotype have lower CR rates following conventional chemotherapy, because of higher mortality in induction and more frequent refractory disease; in addition, CR is shorter when compared to patients with normal karyotype and has limited impact on survival. Accordingly, even when clinically eligible for aggressive chemotherapy, such patients should be included into therapeutic programs based on experimental programs including agents with alternative mechanisms of action. Disclosures: No relevant conflicts of interest to declare.

Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 768-768 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat ◽  
Michael R. McDevitt ◽  
Neeta Pandit-Taskar ◽  
Jorge A. Carrasquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Clinical Activity ◽  
Bone Marrow Blast ◽  
Elimination Kinetics ◽  
Advisory Committees ◽  
Dose Levels

Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Transcriptional and Post-Translational Regulation Of The Bcl-2 Family By IL-6 Mediates Resistance To ABT-737 In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1924-1924 ◽  
Author(s):  
Vikas A. Gupta ◽  
Shannon M. Matulis ◽  
Jason E. Conage-Pough ◽  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Induced Resistance ◽  
Research Funding ◽  
Alternative Pathway ◽  
Mek Inhibitor ◽  
Conditioned Media ◽  
Bone Marrow Niche

Abstract While direct inhibition of Bcl-2 and/or Bcl-xL is an exciting new approach in the treatment of hematologic malignancies, current agents in clinical testing including navitoclax (ABT-263) and ABT-199 are not predicted to be efficacious in most cases of multiple myeloma. Navitoclax and the related molecule ABT-737 promote apoptosis by releasing the pro-apoptotic BH3 only protein Bim from Bcl-2 and Bcl-xL, but are incapable of disrupting the interaction between Bim and Mcl-1, the predominant anti-apoptotic protein in both normal and malignant plasma cells. However, despite their dependence on Mcl-1, some human myeloma cell lines (HMCL) as well as freshly isolated patient-derived myeloma cells are sensitive to ABT-737 in vitro. Knowing that myeloma normally requires the bone marrow niche for survival, we hypothesized that a stromal derived factor might mediate the resistance to ABT-737 in vivo and identified IL-6 as a key resistance factor. In our initial experiments, the HS-5 stromal cell line induced resistance to ABT-737 in the HMCL MM.1s, as did conditioned media from both HS-5 cells and patient derived bone marrow stromal cells. Blocking IL-6 with an IL-6 neutralizing antibody reversed the protective effect of conditioned media, while addition of 10 ng/ml IL-6 protected cells to the same degree as conditioned media. In order to understand the mechanisms of IL-6 mediated resistance to ABT-737, we have focused on the effect of IL-6 on the Bcl-2 family of proteins. In previous work from our lab, the ABT-737 sensitive HMCLs KMS18, MM.1s, and 8226 all showed increased binding of Bim to Bcl-2 and Bcl-xL compared to ABT-737 resistant lines. We therefore examined the effect of IL-6 on the distribution of Bim among Bcl-2, Bcl-xL, and Mcl-1. In KMS18, stimulation with 10 ng/ml IL-6 for 24 hours increases binding of Bim to Mcl-1. The increased binding correlates with a 2 fold increased Mcl-1 expression at both the RNA and protein level. The increased Mcl-1 expression in response to IL-6 may be limited to KMS18 as it was not observed in MM.1s, 8226, or KMS11. IL-6 also does not prevent ABT-737 from disrupting the interaction between Bim and Bcl-xL. We also examined Bim for IL-6 induced post-translational modifications that could alter its binding to Bcl-2 proteins. Bim is known to be phosphorylated on serine 69 by Erk in response to growth factor stimulation. We observed Bim serine 69 phosphorylation within 5 minutes of IL-6 stimulation in both KMS18 and MM.1s cells. Phosphorylation was reversible with 10 μM of the MEK inhibitor U0126. Although serine 69 phosphorylation has been reported to result in Bim degradation, we do not observe any change in Bim levels over the course of 24 hours. Interestingly, the MEK inhibitor sensitized both KMS18 and MM.1s to ABT-737 and was able to partially overcome IL-6 induced resistance. Inhibition of Akt with the PI3K inhibitor LY294002 had no effect on Bim serine 69 phosphorylation or IL-6 induced resistance. Of note, the MEK inhibitor failed to prevent upregulation of Mcl-1 in KMS18, suggesting an alternative pathway mediates this effect. We are currently studying the role of JAK signaling in Mcl-1 expression with the inhibitors AZD1480 and ruxolitinib, and are also extending our results to additional cell lines and patient samples. These results suggest that targeting IL-6 or its downstream pathways may sensitize myeloma to Bcl-2 antagonists such as ABT-199 and navitoclax. Disclosures: Kaufman: Onyx: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy; Jansenn: Consultancy; Merck: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Boise:Onyx Pharmaceuticals: Consultancy.

A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 910-910 ◽  
Author(s):  
Shyamala C. Navada ◽  
Lewis R. Silverman ◽  
Katherine P. Hearn ◽  
Rosalie Odchimar-Reissig ◽  
Erin P. Demakos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
De Novo ◽  
Standard Dose ◽  
Single Agent ◽  
Leukemic Cells ◽  
Bone Marrow Blast ◽  
Recommended Phase Ii Dose

Background: Rigosertib (RIG) is a Ras-mimetic that inhibits the PI3K and PLK cellular signaling pathways by binding directly to the Ras-binding Domain found in Ras effector proteins. It has been tested as a single agent in patients (pts) after failure of hypomethylating agents (HMAs). In vitro, the combination of RIG with azacitidine (AZA) inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (RIG administered prior to AZA) (Skidan et al 2006). Phase I results of this study in pts with MDS or AML showed combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). Phase II was initiated to further study the combination in pts with MDS. Methods: Results from pts in Phase II with MDS previously untreated with an HMA, or who had failed to respond to or progressed on a prior HMA, are presented, while response data from Phase I MDS pts are updated. Pts with CMML are analyzed separately. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy was performed at baseline, day 29, and then every 8 weeks thereafter. Results: The combination of oral RIG and AZA has been administered to a total of 45 pts within Phase I (N=18) and Phase II (N=27). Pts were classified into the following MDS risk categories per the IPSS (Greenberg et al, Blood 1997): intermediate-1 (4), intermediate-2 (10), high-risk (14), and IPSS classification pending (4). Five pts had CMML and 8 had AML. Median age was 66 years; 69% of pts were male; and ECOG performance status was 0, 1, and 2 in 27%, 67%, and 6%, respectively. Twelve pts [MDS (9), CMML (3)] received prior HMA therapy: AZA (11 pts), decitabine (1 pts). Patients have received 1-21+ cycles of treatment to date (median, 3 cycles), with median duration of treatment of 14 weeks. Among 15 evaluable MDS pts treated with the RPTD (1 pt in Phase I, 14 pts in Phase II), marrow responses were observed in 10: marrow CR (mCR) (8), marrow PR (mPR) (2). Responses according to IWG criteria were observed in 10 pts: complete remission (CR) (1), mCR (7), hematologic improvement (HI) (2). Table 1. Responses for MDS Patients Treated at the Recommended Phase II Dose Pt Prior HMA Best BMBL at Nadir1 IWG Response2 Hematologic Improvement 102-008 None mCR mCR Platelet 101-010 None mCR CR Erythroid & Neutrophil 101-011 None mCR mCR None 101-013 None mCR mCR Erythroid 102-010 None SD SD None 101-014 AZA PD PD None 102-011 AZA mPR HI Erythroid & Platelet 101-016 AZA SD SD None 101-017 AZA mCR mCR None 102-013 None NE NE NE 101-019 None SD SD None 101-021 None PD PD None 101-024 None mCR mCR None 101-022 AZA mCR mCR None 101-025 None mCR mCR None 101-026 AZA NE NE NE 101-027 None NE NE NE 102-016 None mPR HI Platelet 1 Silverman et al, Hematol Oncol 2014 2 IWG = International Working Group (Cheson et al, Blood 2006) NE = not evaluable BMBL = bone marrow blast Overall, in pts with MDS treated on Phase I and Phase II, marrow responses were observed in 15 out of 20 evaluable pts: mCR (13), mPR (2). Responses according to IWG 2006 criteria were observed in 14 out of 19 evaluable MDS pts: CR (2), mCR (10), HI (2). Among the 7 evaluable pts with MDS in both the Phase I and Phase II who had failed to respond or progressed on prior treatment with an HMA, 5 had a response after RIG was added: CR (1), mCR (3), HI (1). Analyzed as a separate subgroup, 2 out of 5 (40%) pts with CMML had a mCR. The most frequent adverse events (AEs) in Cycle 1 included nausea (21%) and fatigue (15%), which were also the most frequent AEs in all cycles (fatigue, 28%; nausea, 26%). Six deaths have been observed so far. Three pts were treated for more than 1 year and continue on study. Conclusions: The combination oforalrigosertib and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Marrow CR was observed in 65% of pts, both with de novo MDS and after failure of prior HMA therapy. In pts who received the RPTD, 67% of pts with MDS had a bone marrow blast and IWG response. These results suggest potential synergistic interaction of the combination and support continued study of this unique combination in patients with MDS. Disclosures Silverman: Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Fenaux:CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding. Fruchtman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment.

scholarly journals Anti-Leukemic Activity of Daratumumab in Acute Myeloid Leukemia Cells and Patient-Derived Xenografts

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2312-2312 ◽  
Author(s):  
Cedric Dos Santos ◽  
Shan Xiaochuan ◽  
Zhou Chenghui ◽  
Georges Habineza Ndikuyeze ◽  
Joshua Glover ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cell Killing ◽  
Nsg Mice ◽  
Cd38 Expression ◽  
Acute Myeloid

Abstract Daratumumab is a human antibody that binds to CD38 on the cell surface and induces cell killing by multiple mechanisms including complement mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP) and apoptosis. In pre-clinical and clinical studies, daratumumab has been shown to effectively kill multiple myeloma (MM) cells and to enhance the potency of other treatments against MM. The purpose of the study was to investigate in vitro and in vivo efficacy of daratumumab against 9 acute myeloid leukemia (AML) cell lines and patient-derived samples. First, we evaluated the expression of CD38, complement inhibitory proteins (CIP) CD46, CD55, CD59, and FcgR1 (CD64) on AML cell lines (n=9), AML patient cells (n=10) and healthy donor bone marrow using flow cytometry. CD38 enumeration showed a substantial variation between cell lines (12,827±19, 320 molecules/cell) and between AML patients (11,560±8, 175 molecules/cell), while CD38 expression was more consistent in bone marrow (BM) from healthy donors (1,176±355 molecules/cell). The daratumumab-induced apoptosis observed in cell lines (MOLM-13, MOLM-16, MV-4-11, NB4) in vitro was not correlated with CD38 expression levels. Daratumumab induced minimal ADCC (5-20%) and low levels of (2-5%) CDC mediated cell killing in 6 AML cell lines tested. We did not observe a direct correlation between CD38 expression and ADCC, CDC, nor between CDC and CIP expression. Interestingly, treatment of two human Acute Promyelocytic Leukemia (M3) cell lines HL-60 and NB-4 with all-trans retinoic acid (ATRA) induced a 10-30-fold increase in CD38 expression, suggesting that ATRA could be used in combination with daratumumab. While we, and others, have shown that pre-incubation of primary AML cells with anti-CD38 antibodies inhibits engraftment in NSG mice, we aimed at evaluating the anti-leukemic activity of daratumumab in a therapeutic xenograft model using 3 different AML patients. NSG mice (10/group/patient) were transplanted with T cell-depleted AML cells and BM aspirates were collected 4-6 weeks later to assess leukemia burden in each mouse prior to treatment. Animals were untreated (Ctrl) or received daratumumab (10 mg/kg), or IgG1 isotype once a week for five weeks. We assessed AML burden (% huCD45+ CD33+) in BM, spleen (SPL) and peripheral blood (PB) within 5 days after the last treatment. First, we evaluated an AML (#3406, FLT3-ITD, see figure) with high expression of CD38 (13,445 molecules/cell) and low CD64 (489/cell) was evaluated. Daratumumab significantly reduced leukemia burden in SPL and PB, but had no effect in BM. The same daratumumab-induced reduction in peripheral blasts and lack of effect in BM was observed in 2 other AML patient xenografts (#7577, M1 IDH mutant/FLT3-ITD with 6,529 CD38 molecules/cell; #8096, M2 with 335 CD38 molecules/cell). Interestingly, we observed that daratumumab treatment led to a drastic reduction in CD38 surface expression in AML blasts including in BM, indicating that daratumumab efficiently targeted CD38 in bone marrow blasts. Our results suggest that the bone marrow microenvironment can impair the anti-leukemic activity of daratumumab observed in other tissues. Ongoing xenograft studies are testing whether induction with chemotherapy (Ara-C+doxorubicin), or with other agents disrupting the bone marrow microenvironment, can enhance the anti-leukemic activity of daratumumab. Figure 1: Effect of daratumumab treatment on AML 3406 leukemia burden: Figure 1:. Effect of daratumumab treatment on AML 3406 leukemia burden: Disclosures Dos Santos: Janssen R&D: Research Funding. Xiaochuan:Janssen R&D: Research Funding. Doshi:Janssen R&D: Employment. Sasser:Janssen R&D: Employment. Danet-Desnoyers:Janssen R&D: Research Funding.

scholarly journals Identification of Specific Hnrnps As Novel Therapeutic Targets and Responsive Indicators of KPT330 (selinexor) in Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1657-1657 ◽  
Author(s):  
Adam Cloe ◽  
Li Chen ◽  
Yuan Li ◽  
Hongtao Liu ◽  
Jason X. Cheng
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Nuclear Accumulation ◽  
Protein Accumulation ◽  
Clinical Settings ◽  
Bone Marrow Blast ◽  
Protein Levels ◽  
Small Cohort ◽  
Pre Treatment

Abstract Background: Activenuclear-cytoplasmic shuttling of proteins and RNAs, such as heterogeneous ribonucleoproteins (hnRNPs), is essential for the normal function and survival of eukaryotic cells and tumorigenesis (Dreyfuss et al. 1993 Annu Rev Biochem 62, 289; Gorlich and Mattaj 1996 Science 271, 1513). Up-regulation of exportin 1 (XPO1)/chromosomal maintenance 1 (CRM1), a member of the karyopherin-β family of nuclear export receptor proteins, has been implicated in solid and hematologic malignancies (Kau Kau et al. 2004).Selinexor (KPT-330) has been shown to be able block in vitro and in vivo XPO1/CRM1 functions and is currently in phase-II/IIb clinical trials for treatment of hematologic and solid tumors (Senapedis et al., 2014 Nat Rev Cancer 4, 106). However, the mechanisms underlying the selectivity and efficacy of selinexor are incompletely understood, and no biomarkers are currently available to predict clinical responses to selinexor in clinical settings. In this study, we focus on determining the effects of selinexor on the nuclear-cytoplasmic shuttling of hnRNPs, particularly hnRNPK and hnRNPA1, to elucidate the roles of the hnRNPs in the regulation of selectivity and efficacy of selinexor in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Method:We performed growth inhibition/killing assays, histopathologic evaluations, immunohistochemical studies, subcellular fraction western blotting, super-resolution stimulated emission depletion (STED) confocal microcopy and siRNA knockdown experiments. Results: Our in vitro experiments demonstrate a marked increase in XPO1/CRM1 protein and decrease in TP53 in our azacitidine-resistant MDS/AML cell lines compared to our azacitidine-sensitive MDS/AML cell lines. Selinexor treatment efficiently blocks export of hnRNP K from nuclei and increased nuclear accumulation of hnRNPK and inhibits MDS/AML cell growth, while the protein levels of XPO1/CRM1 and TP53 remain unchanged. Our experiments using clinical bone marrow specimens show no significant difference in the total protein level or nuclear accumulation of XPO1/CRM1 between the normal control and MDS or AML bone marrow specimens. In contrast, a strong positive correlation between MDS/AML disease progression and hnRNPK protein accumulation is observed in those clinical specimens. We have extended our experiments to clinical bone marrow specimens from a small cohort in a clinical trial for selinexor in AML at the University of Chicago (NCT02573363). In our small cohort, 5 patients responded to selinexor, 4 patients did not respond and 1 had a partial response. All 5 responders show a striking decrease in their bone marrow blast percentage from their pre-treatment marrows (average blast percentage 37.4%) to their post-treatment (average blast percentage 1.8%). Non-responders show no such difference in pre and post-treatment blast percentage (56.3 and 57.1%, respectively). Importantly, our experiments demonstrate a marked difference in the protein accumulation and subcellular localization of hnRNPK and hnRNPA1, another member of the hnRNP family, between selinexor-responder and selinexor-non-responder bone marrow specimens. Specifically, selinexor responders had much higher levels of hnRNPK and hnRNPA1 proteins in their pre-treatment bone marrows than non-responders, despite the fact that the latter had higher bone marrow blast percentages on average. There is markedly reduced accumulation of hnRNPK and hnRNPA1 in the post-selinexor treatment bone marrow specimens from the responders, but not the non-responders, suggesting these hnRNPs as key therapeutic targets for selinexor in MDS and AML. In contrast, no significant change in XPO1/CRM1 protein levels is observed in the selinexor-responder vs. selinexor-non-responder bone marrow specimens. Conclusion:Our data have revealed a novel drug-action mechanism by which selinexor impairs the nuclear-cytoplasmic shuttling of hnRNPK and hnRNPA1 in MDS and AML cells. Differential expression and localization of these hnRNPs in normal vs. MDS vs. AML cells may provide the rationale for the preferential killing of leukemia cells by selinexor. Our data also suggest the possibility to develop novel hnRNP-based biomarkers to predict the response to selinexor in clinical settings. Disclosures Liu: Karyopharm: Research Funding; BMS: Research Funding.

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