scholarly journals CUL1: Novel Therapeutic Target in Myeloid Neoplasms Harboring -7/Del(7q)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1281-1281
Author(s):  
Vera Adema ◽  
Cassandra M Kerr ◽  
Sunisa Kongkiatkamon ◽  
Jibran Durrani ◽  
Hassan Awada ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Synthetic Lethality ◽  
Mrna Levels ◽  
Healthy Individuals ◽  
Selective Toxicity ◽  
Advisory Committees ◽  
Proliferative Effect ◽  
Equity Ownership

Lenalidomide (LEN) has established a new paradigm of targeted therapy in MDS. The mechanistic underpinnings of LEN efficacy are related to the synthetic lethality of this agent through its ability to bind cereblon (CRBN). LEN induces degradation of CK1α, which is encoded by the CSNK1A1 gene located on the del(5q) CDR, whereby haploinsufficient levels of this gene allow for selective toxicity to deletion mutants. Another common cytogenetic abnormality present in patients with myeloid neoplasia (MN) is -7/del(7q). To date no selective therapies exist for -7/del(7q), an urgent unfulfilled need, given the poor prognosis associated with this cytogenetic abnormality. We were interested to explore if this same notion of selective toxicity may be possible in del(7q) myeloid patients and sought to screen drugs for this focused population. From a large cohort of patients with MN (n=3,328), we found -7/del(7q) in 10% (n=316) of patients. We first identified a signature pattern of haploinsufficient genes on -7/del(7q) based on NGS. We then searched for haploinsufficient genes which, if targeted by investigational drugs, could provide a therapeutic window for selected MN subtypes in analogy to LEN in del(5q). For the purpose of our analysis, haploinsufficient expression was defined as <25th %tile of the mRNA levels seen in healthy individuals (Kerr, ASH 2019). Among others, we identified haploinsufficiency in CUL1 (7q36.1). CUL1 is a tumor suppressor gene, and is a well-characterized target of neddylation inhibitors. CUL1 had haploinsufficient mRNA levels in 92% of the patients compared to healthy individuals (n=64; log2 CPM 25th %tile expression= 4.966; P<.0001). Similarly, in primary AML (Beat AML; n=37) CUL1 was haploinsufficient in 81% of the cases compared to healthy individuals (n=21; log2 CPM 25th %tile expression= 6.182; P<.0001). Given that the 7q36.1 region involves CUL1 and EZH2, we investigated the interrelation between these 2 genes. Cases with overlapping microdeletions involving CUL1 and EZH2 have been previously described. A 25.4-kb microdeletion encompassing the last exon of EZH2 and the 3′ region of CUL1 has been found in Weaver syndrome, a congenital growth disorder caused by mutations in genes of the PRC2 complex (EED, SUZ12). Distinct from EZH2, CUL1 is rarely mutated in MN; only 2 mutations have been described (TCGAAML: N141S; E241D). Unexpectedly, in our cohort EZH2 had haploinsufficient expression in 97% of the patients compared to healthy individuals (n=64; log2 CPM 25th %tile expression= 6.042; P<.0001). CUL1 and EZH2 low expressors had a significantly (P<.001) higher expression of CDKN1A (p21), another target of neddylation inhibitors. CUL1 low expressors had significantly increased expression of other key cell cycle control factors regulated by CUL1 e.g., p27 (P=.003), c-myc (P=.007), β-catenin (P<.0001), mTOR (P<.0001), as well as the ubiquitin promoter p-IκBα (P=.0017). We previously evaluated the global impact of impairing cullins-neddylation by using MLN4924 (Pevonedistat) on the AML proteome and established a rationale for its combination with azacytidine (AZA) in vivo. MLN4924 elicits an anti-proliferative effect (IC50: 1 μM) in del(7q) AML cells KG-1; an effect that was doubled when MLN4924 was combined with AZA. Available databases of drug sensitivity (cancerrx) summarize the MLN4924 anti-proliferative effect on 721 cancer cells (0.02<IC50 [μM]>97) with sensitivity levels of KG-1 in the lower μM ranges. Our analysis also identified changes in death box-RNA-helicases (DDX41, DDX24,DDX54) and DNA binding proteins (CHD3), opening the possibility that MLN4924 might lead to degradation of key proteins implicated in the pathogenesis of MDS/ AML. The therapeutic index was confirmed by the absence of toxicity to normal CD34+ cells which were unresponsive to MLN4924 because they lack the expression of NEDD8-activating enzyme (NAE) (major target of MLN4924). In contrast to normal cells, NAE is highly expressed in myeloid cancer cells. In an ongoing dose-escalation study of MLN4924 plus AZA, 1 patient with -7 had stable disease after 6 cycles of therapy and 2 patients with del(7q) achieved complete and partial remissions. In sum, we propose that MN with -7/del(7q) abnormalities might represent a patient population genetically hypersensitive to synthetic lethality by neddylation inhibitors. Disclosures Hutter: MLL Munich Leukemia Laboratory: Employment. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Genentech, Verastem: Consultancy; Takeda: Research Funding. Saunthararajah:Novo Nordisk: Consultancy; EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

scholarly journals Bone and Joint Health Markers in Persons with Hemophilia A (PwHA) Treated with Emicizumab in HAVEN 3

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 626-626 ◽  
Author(s):  
Anna Kiialainen ◽  
Markus Niggli ◽  
Christine L. Kempton ◽  
Giancarlo Castaman ◽  
Tiffany Y. Chang ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Study Entry ◽  
Type I ◽  
Healthy Individuals ◽  
Advisory Committees ◽  
Joint Health ◽  
Equity Ownership

Introduction Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that restores the function of missing activated factor VIII (FVIII) by bridging activated FIX and FX in persons with hemophilia A (PwHA). Prophylaxis with emicizumab once weekly or every two weeks resulted in significant reductions in bleeds, including joint bleeds, and a favorable safety profile in PwHA without FVIII inhibitors in the HAVEN 3 study (NCT02847637; Mahlangu et al. 2018). Recurrent joint bleeds in PwHA can lead to hemophilic arthropathy, and hemophilia A has been associated with decreased bone mineral density (Kempton et al. 2014). To explore the potential effect of emicizumab prophylaxis on bone and joint health beyond bleed prevention, we measured joint health scores and bone and joint biomarkers in HAVEN 3. Methods Hemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Week 49 of emicizumab prophylaxis in 107 PwHA in HAVEN 3. Biomarkers of bone formation (osteocalcin [OC], N-terminal propeptide of type I procollagen [P1NP]), bone resorption (C-terminal telopeptide of type I collagen [CTX-I]), osteoblasts (osteoprotegerin), osteoclastogenesis (soluble receptor activator of nuclear factor- kappaB Ligand [sRANKL]), cartilage turnover (cartilage oligomeric matrix protein [COMP]), and inflammation (interleukin 1 beta, interleukin 6, and tumor necrosis factor) were measured in 117 PwHA (Table 1) receiving emicizumab at baseline and after 3, 6, 12, and 18 months of treatment. In all, 94 of 117 PwHA with samples for biomarker analysis were part of the HJHS evaluation. Results PwHA previously on FVIII prophylaxis and those with no target joints at study entry had lower (indicating healthier) HJHS scores at baseline. Mean improvements from baseline of −2.25 (95% confidence interval [CI]: −4.12, −0.39) in total HJHS and −2.23 (95% CI: −4.07, −0.38) in HJHS joint-specific domain (excluding gait) were observed after 49 weeks of emicizumab prophylaxis in PwHA with one or more target joints at study entry (n=71). Improvement was consistent across HJHS for different locations (knee, ankle, elbow). No significant differences in the measured biomarkers between PwHA previously on FVIII prophylaxis or on on-demand treatment, or in those with or without target joints, were seen at baseline. Mean baseline values of most bone and joint biomarkers were within normal ranges, or similar to published levels in healthy individuals, although large variability was observed between individuals. None of the measured biomarkers changed significantly during emicizumab prophylaxis. Higher OC, P1NP, and CTX-I levels were observed in adolescent vs adult PwHA at all time points, which is consistent with reported increases of these biomarkers during skeletal growth. Data suggest a potential association of COMP levels with HJHS scores at baseline (Pearson correlation coefficient 0.46, p=0.0001). Data on two additional cartilage biomarkers, CTX-II (C-terminal telopeptide of type II collagen) and CS-846 (a chondroitin sulfate epitope) are being generated. Conclusions Reduction in joint bleeds was previously reported in HAVEN 3, including over 99% target joint resolution with long-term follow up (Callaghan et al. 2019). This analysis provides further evidence of the positive effect of emicizumab on joint health, showing significant and clinically relevant improvements in HJHS (defined as a ≥2-point reduction in HJHS joints domain [Kuijlaars et al. 2017]) after as few as 49 weeks of emicizumab prophylaxis. The biomarkers measured in blood as surrogates of bone and joint health did not show significant changes over the first 18 months of emicizumab prophylaxis. This may reflect heterogeneity between individuals, and effects on the measured biomarkers by factors other than joint health. However, improvement in bone and joint biomarkers would have been unexpected as the observed means at baseline were already similar to levels reported in healthy individuals. Although data from animal models have suggested that FVIII may play a role in bone health beyond protection against bleeds, in this study we observed no indication of worsening in any of the measured bone and joint health markers that might have resulted from reduced exposure to FVIII in PwHA who switched to emicizumab prophylaxis. Additional data are needed to better understand the long-term effect of emicizumab prophylaxis on bone and joint health. Disclosures Kiialainen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Kempton:Novo Nordisk: Research Funding; Octapharma: Honoraria; Pfizer: Honoraria; Genentech, Inc.: Honoraria. Castaman:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chang:Genentech/Roche: Equity Ownership; Genentech, Inc.: Employment. Paz-Priel:Genentech, Inc.: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Levy:F. Hoffman La Roche: Equity Ownership; Genentech, Inc: Employment.

Effects Of Inhibition Of XPO1/CRM1-Dependent Nuclear Export By Selinexor (KPT-330), Alone and In Combination With Carfilzomib (CFZ), On Apoptosis and Autophagy In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 279-279 ◽  
Author(s):  
Shaun Rosebeck ◽  
Malathi Kandarpa ◽  
Mattina M. Alonge ◽  
Jagoda Jasielec ◽  
Dominik Dytfeld ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Proteasome Inhibition ◽  
Employment Equity ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Equity Ownership

Abstract Introduction Exportin 1 (XPO1/CRM1) is the sole transporter of most tumor suppressor proteins (TSP) from the nucleus to the cytoplasm. Small molecule selective inhibitors of nuclear export (SINE) block XPO1-mediated nuclear export, leading to nuclear retention of TSP, inducing cancer cell death and sensitizing cancer cells to other cytotoxic drugs. Although the cytotoxic and apoptotic effects of SINE on different cancer cells have now been established, the mechanism of cell death is still not fully understood. Recently, autophagy emerged as a possible cell death pathway and alternate to the ubiquitin-proteasome pathway (UPP) by which excess and/or dysfunctional proteins and organelles are degraded and recycled. MM cells require basal autophagy for survival and caspase 10 protease activity is required to limit autophagic cell death. The possibility that autophagy may be involved in the mechanism of action of SINE is supported by observations that knockdown of XPO1 can promote autophagy and that cytoplasmic p53 can repress autophagy. In this study, we evaluated the contribution of autophagy to the effects of Selinexor (KPT-330), a SINE currently in two phase I clinical trials, on MM cell cytotoxicity. Because proteasome inhibition can also induce autophagy, we hypothesized that the combination of Selinexor and CFZ, a next generation irreversible proteasome inhibitor approved for treatment of MM, may synergistically augment cytotoxicity in MM cells. Methods Plasma cells (PC) were purified from consented MM patient bone marrow aspirates using EasySep (Stem Cell Technology). PC purity (>80%) was determined by Wright-Giemsa staining of cytospins. Human myeloma cell lines (HMCL) NCI-H929, RPMI-8226, MM1.S and MM1.R were cultured in RPMI1640 with 10% FBS. IC50 values were determined using GraphPad Prism. Drug combination efficacy was determined using CalcuSyn (Biosoft). Combination index (CI) values <1.0 indicate synergy. Transcription factor profiling plate array II was from Signosis (Sunnyvale, CA). Otherwise, our studies used standard cellular and molecular biology techniques. Results Selinexor caused significant cytotoxicity in HMCL (IC50 10-100 nM), induced cell cycle arrest in G1, and promoted apoptotic cell death typified by caspase activation, DNA fragmentation, and Annexin V binding. Importantly, purified PC from newly-diagnosed MM patients were also sensitive to the cytotoxic effects of Selinexor. HMCL treated with KPT-330 also exhibited nuclear retention of p53. To gain insight into more global effects of SINE treatment, we assayed DNA binding activity of approx. 100 different transcription factors. TSP, such as Rb, p53, and EGR-1, exhibited increased activity, whereas proto-oncogenes, including NF-κB, Myc, and Myb, were inactivated in response to KPT-330. Western blot analysis of inactivated targets showed nearly total loss of protein. Unlike XPO1, which is degraded via the UPP upon treatment with SINE, loss of Myc and NF-κB subunits, including RelA, RelB, and p52, could not be reversed by proteasome inhibition. Instead, we found that Selinexor treatment induced markers of autophagy, including LC3B induction and processing, and promoted loss of caspase 10, which is associated with autophagic cell death in MM. Importantly, we have determined that the combination of Selinexor and CFZ results in synergistic cell death (CI 0.2-0.6) characterized by enhanced induction of both apoptosis and autophagy in HMCL. The effects of Selinexor and CFZ were also evaluated in NOD-SCID mice inoculated subcutaneously with NCI-H929 cells. Mice were treated 3 times weekly per oswith Selinexor (5 or 10 mg/kg) alone and in combination with twice-weekly IV-administered CFZ (1.5 or 3 mg/kg). After 16 days of treatment, high doses of either CFZ or Selinexor alone moderately inhibit tumor growth. Treatment with the combination of CFZ and Selinexor at all dose levels was more effective than single agent treatment, and high dose combination treatment completely impaired xenograft tumor growth with good tolerability. Conclusion Our studies are the first to suggest that Selinexor-induced cell death correlates with both apoptosis and autophagy, and that both cell death pathways are enhanced in response to combined treatment with CFZ. Overall, our pre-clinical study provides strong rationale for evaluation of Selinexor in combination with CFZ for the treatment of MM. Disclosures: McCauley: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals TP73 Isoforms (TAp73 and ΔNp73) Are Overexpressed in Acute Myeloid Leukemias and Potential Therapeutic Targets to Enhance Anti-Leukemia Activities of Bcl-2 and MDM2 Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2629-2629
Author(s):  
Yuki Nishida ◽  
Jo Ishizawa ◽  
Vivian Ruvolo ◽  
Michael Andreeff
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Hematopoietic Cells ◽  
Mrna Levels ◽  
Advisory Committees ◽  
Myeloid Leukemias ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Mdm2 Inhibitor

Abstract Background TP73 is one of the TP53 family transcription factors and generates two isoforms, the transactivation p73 (TAp73) and the N-terminally truncated ΔNp73. TAp73 shares a homologous N-terminal activation domain with p53 and has similar pro-apoptotic function to p53. ΔNp73 lacks an activation domain and has activities distinct from TAp73. ΔNp73 has a dominant negative effect on the DNA binding of TAp73 and more importantly, of p53, since the DNA binding domain is homologous with that of TAp73 and highly similar to that of p53. In acute myeloid leukemias (AML), TP73 has been reported to be expressed except in acute promyelocytic leukemias. However, the association of TP73 isoforms with clinical and genetic characteristics and the regulation of the isoforms in AML have not been explored. Results We determined copy numbers of ΔNp73 and TAp73 mRNA levels in 78 AML samples including 31 de novo AML using droplet digital PCR (ddPCR), which allows to determine the absolute quantity of the isoforms expressed, and investigated their clinical and biological relevance. ΔNp73 and TAp73 expression was detected in 93.6% and 98.7% of AML samples at variable levels (mean ± SEM, 10.6 ± 5.0, and 106.6 ± 33.7 copies/µL, for ΔNp73 and TAp73, respectively). ΔNp73 and TAp73 mRNA levels were highly correlated (R2 = 0.72, P < 0.0001). Normal peripheral blood mononuclear cells and CD34+ hematopoietic cells showed little or no ΔNp73 and TAp73 expression (0.09 ± 0.09 and 0.42 ± 0.35 copies/µL, respectively), demonstrating that expression of ΔNp73 and TAp73 is 100 - 1,000 fold higher in AML as compared to normal hematopoietic cells. These data collectively suggests that transcriptional systems of both isoforms in AML cells are abnormally activated. Disease status (de novo or relapsed/refractory) and cytogenetic abnormalities did not correlate with ΔNp73 and TAp73 levels. However, AML with IDH1/2 mutations had 8.5-fold lower ΔNp73 expression than those with wild-type IDH1/2 (1.8 ± 0.8 vs 15.4 ± 7.7 copies/µL, P = 0.0069), with a similar trend for TAp73 (49.0 ± 20.3 vs 138.6 ± 51.4 copies/µL, P = 0.056). For de novo AML samples, those with DNMT3a and NRAS mutations had significantly higher ΔNp73, but not TAp73, than those without these mutations (21.6 ± 18.2 vs 2.5 ± 1.2 copies/µL, P = 0.017 and 5.6 ± 2.5 vs 9.7 ± 8.0 copies/µL, P = 0.047, respectively). These findings suggest that ΔNp73 and TAp73 can be differentially regulated in AML based on mutation status. To further explore the regulation of TP73 isoforms, we used MDM2 inhibitor Nutlin-3a to induce p53 which is a transcriptional inducer of ΔNp73. Indeed, MDM2 inhibition increased p73 protein levels, and knockdown of both TAp73 and ΔNp73 in AML cells enhanced apoptosis induction by Nutlin-3a (specific annexin V induction by 5 uM Nutlin-3a, 21.9 ± 1.3% vs 61.3 ± 5.2%, P = 0.0084 in OCI-AML3 cells with vector control vs Shp73, respectively), possibly due to the silencing of ΔNp73. AML cells with IDH1/2 mutations are more dependent on Bcl-2 than those without (Chan, Nat Med 2015). Intriguingly, (R)-2HG, the oncometabolite of mutant IDH1/2, reduced both TAp73 and ΔNp73 in AML cells and increased susceptibility to the Bcl-2 inhibitor ABT-199. These results imply a potential mechanism that regulates p73 isoforms by histone methylation or other epigenetic modifications in AML. Conclusion Absolute quantitation of TP73 isoforms by ddPCR revealed high expression in AML cells compared to normal hematopoietic cells. The repressed expression of TP73 isoforms in AML cells with IDH1/2 mutations or by the oncometabolite (R)-2HG suggests that epigenetic modifications through (R)-2HG can regulate TP73 transcription and enhance the anti-leukemia effect by Bcl-2 inhibition. Finally, downregulation of TP73 isoforms enhances the efficacy of MDM2 inhibitor in AML, suggesting a potential therapeutic strategy to enhance MDM2 inhibitor-mediated p53 activation. Disclosures Andreeff: Amgen: Consultancy, Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Astra Zeneca: Research Funding; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Reata: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding.

Preliminary Evidence Of Anti Tumor Activity Of Selinexor (KPT-330) In a Phase I Trial Ofa First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) In Patients (pts) With Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 90-90 ◽  
Author(s):  
John Kuruvilla ◽  
Martin Gutierrez ◽  
Bijal D. Shah ◽  
Nashat Y. Gabrail ◽  
Peter de Nully Brown ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Study Entry ◽  
Mrna Levels ◽  
Tumor Shrinkage ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background Exportin 1 (CRM1/XPO1) is the exclusive transporter of the majority of Tumor Suppressor Proteins (TSP) out of the nucleus, rendering these TSPs non-functional. Selinexor (KPT-330) is a potent, oral SINE XPO1 antagonist, forcing the nuclear retention and activation of >10 TSPs resulting in NHL and CLL cell death in vitro, while sparing normal lymphocytes and other hematopoietic cells. Oral Selinexor has marked activity in murine models of NHL and CLL including R-CHOP resistant tumors. Dogs with spontaneous B- and T-cell lymphomas exposed to the related SINE Verdinexor demonstrate potent anti tumor effect and good tolerability. Methods Patients (pts) with advanced NHL or CLL relapsed/refractory to all available drug classes were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a Phase 1 trial in hematological malignancies (NCT01607892). Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were obtained. Response evaluation was performed every cycle. Results 18NHL/CLL pts with median age 66.5yrs; ECOG PS 0/1: 8/10; median number of prior regimens: 4.5 [range 2-11], received KPT-330 across 6 dose levels (3 to 30 mg/m2). Ten pts experienced drug-related grade 3/4 Adverse Events (AEs) including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), fatigue (n=1). The most common grade 1/2 toxicities were: anorexia (10/18pts; 56%), fatigue (9/18; 50%), diarrhea (6/18; 33%), vomiting (6/18; 33%), neutropenia (5/18; 28%), malaise (3/18; 17%), anemia (3/18; 17%) and weight loss (3/18; 17%). These adverse events were manageable with supportive care. 23mg/m2, one case of Grade 4 thrombocytopenia for >5 days without bleeding was reported as a DLT for the cohort; this patient with refractory follicular NHL was continued on therapy at the same dose and schedule with intermittent platelet support with SD for 83 days on study.Dose escalation continues.There were no clinically significant cumulative toxicities or major organ dysfunction and pts have remained on therapy for ≥6 cycles. Maximum tolerated dose has not been reached; dosing at 35 mg/m2 twice weekly is ongoing.PK analysis at doses of 3-35 mg/m2demonstrated a dose proportional increase in Cmax and AUC with increasing dose. Elimination half-life was independent of dose and ranged from 4.7-7.0 hours. Significant increases (2-20x) in total leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction.Evaluation of lymph node biopsies from 2 pts confirms Selinexor-induced nuclear localization of multiple TSPs as well as apoptosis of tumor cells. Response was evaluable in 15pts; Selinexor treatment induced tumor shrinkage or disease stabilization in 80%(n=12) of pts with relapsed/refractory NHL/CLL who had progressive disease on study entry (Figure 1). 20% (n=3) of pts had clinical progression. One patient with ibrutinib-refractory CLL with Richter's transformation who progressed on chemotherapy achieved a rapid 60% reduction in lymph nodes in Cycle 1 and was referred for transplantation. A patient with DLBCL refractory to R-CHOP and bone marrow transplantation achieved a near CR (93% tumor shrinkage) and remains on study >11 months. Conclusions Oral Selinexor is generally well tolerated, with favorable PK andPDn parameters. In this cohort of heavily pretreated, refractory/refractoryNHLand CLL with progressive disease on study entry, single agent oral Selinexor induced tumor shrinkage in the majority of pts. Disclosures: Kuruvilla: Seattle Genetics: Consultancy, Honoraria, Research Funding; Hoffman LaRoche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shah:Seattle Genetics, Inc.: Research Funding; NCCN: Membership on an entity’s Board of Directors or advisory committees; SWOG: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau. Garzon:Karyopharm: Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Speakers Bureau. Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Rashal:Karyopharm Therapeutics: Employment, Equity Ownership. Yau:NPM Pharma Inc: NPM Pharma hired Ozmosis Research as CRO for this trial Other. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. McCartney:Karyopharm Therapeutics: Employment, Equity Ownership. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therapeutics: Employment. Pond:Ozmosis Research: Consultancy. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Mirza:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals TP73 As Novel Determinant of Resistance to BCL-2 Inhibition in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1251-1251
Author(s):  
Yuki Nishida ◽  
Jo Ishizawa ◽  
Vivian Ruvolo ◽  
Feng Wang ◽  
Koichi Takahashi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Mrna Levels ◽  
Wild Type ◽  
Advisory Committees ◽  
Protein Levels ◽  
Enhanced Sensitivity ◽  
Equity Ownership ◽  
Acute Myeloid

Background. BCL-2 inhibition is a novel and highly effective treatment modality in acute myeloid leukemias (AML). AML patients with IDH1/2 mutations are highly sensitive to BCL-2 inhibition by venetoclax (VEN) (Chen et al Nat Med 2015). High expression levels of the BCL-2 family proteins MCL-1 or BCL-XL, or knockout of TP53 have been reported to confer resistance to BCL-2 inhibition (Pan et al. Cancer Cell 2017, Nechiporuk et al. Cancer Discov 2019). p73 is one of the p53 family transcription factors and generates two isoforms, transactivation p73 (TAp73) and the N-terminally truncated ΔNp73. TAp73 shares a homologous N-terminal activation domain with p53 and has pro-apoptotic function similar to p53. ΔNp73 lacks an activation domain and has a dominant negative effect on the DNA binding of TAp73 and more importantly, of p53.TP73 is expressed in AML except in acute promyelocytic leukemias. However, the associations of TP73 isoforms with clinical and genetic characteristics or sensitivity to BCL-2 inhibition in AML have not been explored. Results. We determined copy numbers of TAp73 and ΔNp73 mRNA levels in AML samples (N = 78) and normal CD34+ hematopoietic cells (HPC) using droplet digital PCR and investigated their clinical and biological relevance. Both TP73 isoforms were expressed in AML, with TAp73 expression being 50-fold higher in AML than in CD34+ HPC (P = 0.027); no difference seen for ΔNp73 (P = 0.80), suggesting that TAp73 is aberrantly expressed in AML cells. ΔNp73 and TAp73 mRNA levels were highly correlated (R2 = 0.72, P < 0.0001). AML samples had 10-fold more abundant TAp73 than ΔNp73 mRNA levels (P = 0.0017) and isoforms were not associated with disease status (de novo vs relapsed/refractory) or cytogenetic groups, and were mutation-agnostic, except for IDH1/2. IDH1/2 mutant AML showed lower levels of TAp73 and ΔNp73 than those with wild-type IDH1/2 (P = 0.06 and P = 0.007 for TAp73 and ΔNp73, respectively). In a separate dataset, we observed repressed TP73 in IDH1/2 mutant vs. wild-type AML samples (P = 0.073) by RNAseq analysis (N = 47). Mechanistically, treatment with cell permeable octyl-(R)-2HG, the oncometabolite of mutant IDH1/2, reduced both TAp73 and ΔNp73 and increased susceptibility to VEN. Lentiviral knockdown of p73 in OCI-AML3 cells resulted in enhanced sensitivity to VEN with no significant changes in MCL-1 and p53 protein levels, or TP53 targets (MDM2, CDKN1A, FAS and BBC3). VEN resistant AML cells (MOLM-13 and MV4;11) generated through long-term culture with VEN expressed highly elevated TP73 mRNA and protein levels without significant changes in p53 or TP53 target changes, suggesting that elevated p73 could confer resistance to VEN independent of p53 function (Figure). Knockdown of TP73 showed increased protein levels of SDHB, UQCRC2 and ATP5A, components of mitochondrial respiratory chain complex II, III and V, indicating increased dependency on oxdative phosphorylation by depleting p73. Overexpression of TAp73α by lentiviral gene transfer minimally increased VEN-induced apoptosis, while ΔNp73γ overexpression conferred striking resistance to VEN in MOLM-13 cells, suggesting p73 isoform-specific dependency of VEN sensitivity/resistance. The combination of 5'-azacitidine (5'-aza) and VEN decreased ΔNp73 level by 50%. Conclusion. Repression of TP73 in IDH1/2 mutant AML, and downregulation of TP73 by the oncometabolite 2-HG were associated with enhanced sensitivity to VEN, suggesting that TP73 determines AML susceptibility to BCL-2 inhibition. VEN resistant cells massively overexpressed TP73, and TP73 knockdown restored sensitivity to VEN. Specifically, overexpression of the ΔNp73γ isoform resulted in induced VEN resistance. ΔNp73 levels were also reduced by combining VEN with 5'-aza. Results may explain the high sensitivity of IDH1/2 mutant AML to VEN as consequence of downregulation of TP73 by 2-HG, and establish the mechanism of synergistic effect by VEN + 5'-aza combination and overexpression of p73 as a novel resistance mechanism to BCL-2 inhibition. Disclosures Ishizawa: Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Takahashi:Symbio Pharmaceuticals: Consultancy. Carter:Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Oncolyze: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Fold Change ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

scholarly journals Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 266-266
Author(s):  
Sagar Patel ◽  
Saulius K. Girnius ◽  
Binod Dhakal ◽  
Lohith Gowda ◽  
Raphael Fraser ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Disease Status ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Primary Plasma Cell Leukemia ◽  
Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score &gt;90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

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