19 research outputs found
Efficacy and safety of avapritinib in advanced systemic mastocytosis:interim analysis of the phase 2 PATHFINDER trial
Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10(-9)), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM
Class II Transactivator (CIITA) Enhances Cytoplasmic Processing of HIV-1 Pr55Gag
The Pr55(gag) (Gag) polyprotein of HIV serves as a scaffold for virion assembly and is thus essential for progeny virion budding and maturation. Gag localizes to the plasma membrane (PM) and membranes of late endosomes, allowing for release of infectious virus directly from the cell membrane and/or upon exocytosis. The host factors involved in Gag trafficking to these sites are largely unknown. Upon activation, CD4+ T cells, the primary target of HIV infection, express the class II transcriptional activator (CIITA) and therefore the MHC class II isotype, HLA-DR. Similar to Gag, HLA-DR localizes to the PM and at the membranes of endosomes and specialized vesicular MHC class II compartments (MIICs). In HIV producer cells, transient HLA-DR expression induces intracellular Gag accumulation and impairs virus release.Here we demonstrate that both stable and transient expression of CIITA in HIV producer cells does not induce HLA-DR-associated intracellular retention of Gag, but does increase the infectivity of virions. However, neither of these phenomena is due to recapitulation of the class II antigen presentation pathway or CIITA-mediated transcriptional activation of virus genes. Interestingly, we demonstrate that CIITA, apart from its transcriptional effects, acts cytoplasmically to enhance Pr160(gag-pol) (Gag-Pol) levels and thereby the viral protease and Gag processing, accounting for the increased infectivity of virions from CIITA-expressing cells.This study demonstrates that CIITA enhances HIV Gag processing, and provides the first evidence of a novel, post-transcriptional, cytoplasmic function for a well-known transactivator
Incorporating measurable (‘minimal’) residual disease-directed treatment strategies to optimize outcomes in adults with acute myeloid leukemia
Mini‐HCVD plus inotuzumab plus or minus blinatumomab: Hype or hope?
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151845/1/cncr32381_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151845/2/cncr32381.pd
Successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction
Utility of methicillin‐resistant Staphylococcus aureus (MRSA) nasal screening in patients with acute myeloid leukemia (AML)
BackgroundCurrent literature has demonstrated the utility of the MRSA nasal screen as a de‐escalation tool to decrease unnecessary anti‐MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking.MethodsThis is a single‐center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without a history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia.ResultsOf 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%.ConclusionsGiven the low prevalence, empiric use of anti‐MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti‐MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de‐escalate anti‐MRSA antibiotics in patients with AML with or without HCT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170282/1/tid13612.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170282/2/tid13612_am.pd
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A Phase 2a Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Myelofibrosis
Ruxolitinib (Jakafi®) is the one approved therapy for myelofibrosis (MF) based on reduction of splenomegaly and symptoms but JAK inhibition has not proven to significantly modify disease progression. There remains the need for novel therapies with distinct modes of action that can improve the patient experience of MF and impact progression. Lysine-specific demethylase, LSD1, is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors. LSD1 bound to GFI1b permits maturation of progenitors to megakaryocytes and enables their normal function. IMG-7289 (bomedemstat) is an orally available LSD1 inhibitor. In mouse models of myeloproliferative neoplasms (MPN), IMG-7289 reduced elevated peripheral cell counts, spleen size, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting its clinical development. IMG-7289-CTP-102 is an ongoing, multi-center, open-label study that recently transitioned from a Phase 1/2a dose-range finding study to a Phase 2b study of IMG-7289 administered orally once-daily in adult patients with intermediate-2 or high-risk MF resistant to or intolerant of ruxolitinib. The key objectives are safety, PD, changes in spleen volume (MRI/CT) and total symptoms scores (TSS) using the MPN-SAF instrument. Inclusion criteria included a platelet count ≥100K/μL. Bone marrow (BM) biopsies and imaging studies (both centrally-read) were conducted at baseline and during washout (post-Day 84). The MPN-SAF was self-administered weekly. Phase 1/2a patients were treated for 84 days followed by a washout of up to 28 days. Patients demonstrating clinical benefit could resume treatment for additional 12 week cycles. Dosing was individually tailored using platelet count as a biomarker of effective thrombopoiesis. Patients were started at a presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL. This preliminary analysis includes 20 patients; 18 enrolled in the Phase 1/2a study, 2 in the Phase 2b portion. 50% had PMF, 35% Post-ET-MF, 15% Post-PV-MF. The median age was 65 (48-89) with 70% males. The median baseline platelet count was 197 k/μL (102-1309k/μL). 12 patients (56%) were transfusion-dependent at baseline. Sixty percent were IPSS-classified as high risk, the remainder, intermediate risk-2. 71% had more than 1 mutation of the 261 AML/MPN genes sequenced of which 63% were high molecular risk (ASXL1, U2AF1, SRSF2) mutations; 31% had abnormal karyotypes. Sixteen patients completed the first 12 weeks; 4 patients withdrew, one due to fatigue (Day 33), one for progressive disease (Day 39), one due to physician decision (Day 76), one for an unrelated SAE of cellulitis (Day 83). All patients were up-titrated from the starting dose 0.25 mg/kg to an average daily dose of 0.89 mg/kg ± 0.20 mg/kg, the dose needed to achieve the target platelet count range; 17 achieved the target platelet range in a mean time of 45 days. Of patients evaluable for response after cycle 1 in Phase1/2a (N=14), 50% had a reduction in spleen volume from baseline (median SVR: -14%; -2% to -30%). Further, 79% (N=11) recorded a reduction in TSS (mean change -28%; -13% to -69%); for 21% of patients (N=3), the change was >-50%. Improved BM fibrosis scores at Day 84 were observed in 2/13 patients. Two patients had improvement in transfusion requirements. Plasma IL-8 levels were significantly elevated in 6/14 patients at baseline and dropped in a dose-dependent manner over 21 days in 5/6 patients. The mean duration of treatment is 166 days (14-539) at the census point in this ongoing study. Nineteen patients (95%) reported 358 AEs of which 22 were SAEs. Of the SAEs, 2 were deemed by investigators as possibly related: painful splenomegaly and heart failure. There have been no safety signals, DLTs, progression to AML, or deaths. This is the first clinical study of an LSD1 inhibitor in patients with MPNs. Once-daily IMG-7289 was well-tolerated in a heterogeneous population of patients with advanced MF and limited therapeutic options. Despite under-dosing and slow dose escalation, IMG-7289 improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients. The Phase 2b 24-week expansion study with more aggressive dosing aimed at preserving safety and enhancing efficacy is open for enrollment in the US, UK and EU. Figure Disclosures Pettit: Samus Therapeutics: Research Funding. Gerds:Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy. Yacoub:Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Natsoulis:Imago BioSciences: Consultancy, Equity Ownership. Jones:Imago BioSciences: Employment, Equity Ownership. Talpaz:Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding. Peppe:Imago BioSciences: Employment, Equity Ownership. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rienhoff:Imago Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties
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Outcomes of Patients with Accelerated/Blast-Phase Myeloproliferative Neoplasms in the Current Era of Myeloid Therapies
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A Phase 2 Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Advanced Myelofibrosis
Abstract
There is an unmet need for novel therapies with distinct modes of action to offer clinical benefit for patients with myelofibrosis (MF) who become resistant or intolerant to JAK inhibitors. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal potential of malignant myeloid cells for hematopoietic differentiation, e.g., LSD1 licenses maturation of megakaryocytes, one cell type critical to the pathogenesis of MF. Bomedemstat is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis, mutant cell burden and overall survival (Jutzi et al. 2018). IMG-7289-CTP-102 is a global, open-label Phase 1/2 study evaluating bomedemstat dosed once daily in MF patients (NCT03136185). Data from this ongoing study are presented.
Key eligibility criteria include IPSS int.-1 or -2 or high-risk patients refractory or resistant to, inadequately controlled by or intolerant of available approved therapy, or in the Investigator's judgment, are not candidates for available approved therapy, peripheral blast count ≤10%, absolute neutrophil count ≥0.5 x 10 9/L, and platelet count ≥100 x 10 9/L. Key objectives are safety and reduction of spleen volume (SVR) by MRI/CT and total symptoms scores (TSS) using the MPN-SAF instrument. Serial bone marrow (BM) biopsies and imaging studies are read centrally. Of 261 genes recurrently mutated in AML/MPN/MDS, germline and somatic baseline and follow-up sequencing is conducted to quantify existing or new mutant alleles frequencies (MAF). Dosing is individually tailored using platelet count as a biomarker of bomedemstat activity on megakaryocyte function, targeting a range between 50-100 x 10 9/L and titrating as needed.
At data cutoff (15 July 2021), the study is fully enrolled with 89 patients: 49% primary MF, 30% post-essential thrombocythemia-MF, 21% post-polycythemia vera-MF. Median age is 68 (35-88) with 52% males. Prior treatment with ruxolitinib was reported in 81% (72/89), 43% (38/89) had also received up to 3 different treatments. 30% of patients (25/83) had received ≥1 RBC transfusion prior to dosing. By IPSS, 54% were high-risk, 40% int.-2, and 6% int.-1. At screening (N=88), sequencing to an average depth of >1000, JAK2 was mutated in 70%, CALR in 22%, and MPL in 7%; 64% had ≥2 mutations of which 66% had high-molecular risk mutations in ASXL1, IDH1/2, EZH2 and/or SRSF2.
The median duration of treatment is 17 weeks (2-102). Of all enrolled patients for whom data is available (evaluable) at 24 weeks for TSS with baseline value ≥20, 89% recorded a reduction in TSS (mean change -36%; -81% to 21%) with 39% reporting ≥50% reduction. Of all patients evaluable for SVR at 24 weeks (N=27), 78% had a reduction in spleen volume from baseline (mean SVR: -4%; -41% to 107%) with 37% showing ≥20% SVR. Of evaluable patients (N=29), 86% had stable (∆1.0 g/dL). Of patients evaluable for BM fibrosis scoring post-baseline (N=29), 17% improved by 1 grade and 66% were stable. Serially sequencing 43 patients, MAFs in one or more alleles were reduced in 42% with 1 patient in complete molecular remission, and stable in 44%. Clones with JAK2 and/or ASXL1 mutations were most frequently reduced. MAF reduction also correlated with efficacy: SV and/or TSS were improved in patients in whom MAFs were also decreased. No new mutations were identified in any patient. No patient transformed to AML during this study.
The most common non-hematologic AEs reported by patients were diarrhea and dysgeusia, each at 28% (25/89). There have been 13 related SAEs with 3 Grade 2, 9 Grade 3 and 1 Grade 4 (thrombocytopenia). Thirty-nine patients remain on study. Early terminations (<24 weeks) due to AEs occurred in 13 (15%) patients with 5 related to bomedemstat, and 15 discontinued for other reasons. There have been no safety signals, DLTs, or deaths related to drug.
In a patient population with advanced disease, a heavy mutation burden and limited treatment options, once-daily bomedemstat as monotherapy had an acceptable tolerability profile, relieved symptoms, reduced spleen volume and improved anemia without any significant safety signals. Additionally, reductions in the allele frequency of both driver and high molecular risk mutations were observed and correlated with improved efficacy metrics.
The study is now fully enrolled and additional data will be presented.
Disclosures
Yacoub: Cara: Current equity holder in publicly-traded company; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in publicly-traded company. Bradley: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gerds: AbbVie: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; PharmaEssentia Corporation: Consultancy; Constellation: Consultancy; Novartis: Consultancy. Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Mead: Abbvie: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau. Göthert: AOP Orphan Pharmaceuticals: Honoraria, Other: Travel reimbursement; zr pharma&: Honoraria; Proteros Biostructures: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel reimbursement; Incyte: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel reimbursement. Koschmieder: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Abbvie: Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Image Biosciences: Other: Travel support; Alexion: Other: Travel support; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Karthos: Other: Travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding. Jones: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Peppe: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Natsoulis: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Hong: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months. Harrison: BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Incyte Corporation: Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or a