ALBERT

Beschreibung: BCL6 is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed induction of BCL6 repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitor induced apoptosis and decreased colony forming capacity which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in significant reduction of leukemia initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal HSCs. Treatment with cytarabine (AraC) further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML patient derived xenografts (PDX) with BCL6 inhibitor plus Ara-C suggested enhanced anti-leukemia activity by this combination. Hence pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.

Beschreibung: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Beschreibung: Exhaled carbon monoxide (COex) level has been proposed as a noninvasive and easily-obtainable cardiovascular risk marker, however, with limited prospective evidence, and its association with stroke risk has been rarely explored. Measurements of COex were performed during 2004–2008 baseline examinations in the China Kadoorie Biobank study among 512,891 adults aged 30–79 years from 10 diverse study areas. After excluding participants with baseline cardiopulmonary diseases, stroke and cancer, 178,485 men and 267,202 women remained. Cox regression yielded hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of cardio-cerebral-vascular disease (CCVD) associated with COex levels, with sequential addition of adjustment for proxy variables for CO exposure, including study area indexing ambient CO variations at large, and smoking and solid fuel use, apart from adjusting for traditional cardiovascular risk factors. During 7-year follow-up, we documented 1744 and 1430 major coronary events (myocardial infarction plus fatal ischemic heart disease), 8849 and 10,922 ischemic strokes, and 2492 and 2363 hemorrhagic strokes among men and women, respectively. The HRs with 95% CIs comparing the highest with lowest COex quintile were 2.15 [1.72, 2.69] for major coronary events, 1.65 [1.50, 1.80] for ischemic stroke, and 1.35 [1.13, 1.61] for hemorrhagic stroke among men, while among women higher associated risk was only observed for major coronary events (1.64 [1.35, 2.00]) and ischemic stroke (1.87 [1.73, 2.01]). The elevated risks were consistent when COex level was over 3 ppm. However, these associations were all attenuated until null by sequential addition of stratification by study areas, and adjustments of smoking and solid fuel use. Nevertheless, the association with ischemic stroke was maintained among the subgroup of male smokers even with adjustment for the depth and amount of cigarette smoking (HR [95% CI]: 1.37 [1.06, 1.77]), while a negative association with hemorrhagic stroke also appeared within this subgroup. Higher COex level (over 3 ppm) was associated with elevated risk of ischemic CCVD, but not independently of CO exposure. Our finding suggests that, though not an independent risk factor, COex could potentially provide a cost-effective biomarker for ischemic cardio-cerebral-vascular risk, given that CO exposure is ubiquitous.

Beschreibung: INTRODUCTION: Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma (AITL), is characterized by recurrent mutations affecting epigenetic regulators such as TET2, DNMT3A, IDH2 and RHOA. The association of aberrant DNA methylation with lymphomagenesis provides rationale for clinical application of hypomethylating agents. Azacitidine, an epigenetic modifier which inhibits DNA methyltransferase, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the findings of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). METHODS: This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Priming with oral azacitidine (CC-486) at 300 mg daily was administered for 7 days prior to cycle 1 of CHOP, and for 14 days before CHOP cycles 2-6. Supportive care included mandatory G-CSF. The primary endpoint is CR per 2014 IWG criteria. Secondary endpoints include ORR, safety and survival. Correlative biomarker studies are planned to assess genomic mutations by next-generation-sequencing (NGS), in addition to methylation and transcription profiles. Using a Simon two-stage design comparing an CR of ≥60% with treatment to an unacceptable CR of ≤35% (alpha=10%, power=80%), 9 or more CR out of 17 enrolled patients were required to declare the treatment worthy of further study. RESULTS: From 6/2018 to 3/2020, 21 subjects with previously untreated PTCL were enrolled at 4 centers, and the study met its accrual. At study entry, 17 patients (81%) had PTCL-TFH (16 AITL and 1 TFH), 3 with PTCL-NOS, 1 with ATLL, including 5 (24%) with CD30+ disease. The median age was 66 years (range 22-77), and the M:F ratio was 1.6:1. Nineteen (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (33%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (71.4%), thrombocytopenia (9.5%) and anemia (14.3%), with febrile neutropenia uncommon (14.3%). Grade 3-4 non-hematologic toxicities included fatigue (14.3%), hyponatremia (14.3%), diarrhea (4.8%), vomiting (4.8%), rash (4.8%), and elevated ALT (4.8%). One incidence each of influenza A, COVID-19 pneumonia, C.diff and strongyloides hyperinfection were observed and treated. There was no study treatment-related mortality to date. As of July 2020 at a median follow-up of 7 months (range 4-25 months), one subject withdrew consent after cycle 1 (patient preference), and 20 subjects had at least one response assessment, including 15 completed treatment, 2 progressed during treatment, and 3 nearing completion of therapy. At interim assessment after cycle 3 (n=20), the ORR was 85% with CR at 55% (90%CI of 34.7%-74.1%). To date, the preliminary end-of-treatment (EOT, n=17) CR was 76.5% (90%CI of 53.9%-91.5%) for all evaluable patients and was 86.7% for 15 PTCL-TFH, exceeding primary endpoint threshold. CR did not correlate with CD30 expression. The estimated 1-yr PFS for all patients was 56.8% (95%CI of 26.3%-87.3%), with 1-yrs PFS for PTCL-TFH at 61.1% (95%CI of 29.5%-92.7%), and the estimated 1-yr OS for all patients was 74.4% (95%CI of 48.8%-100.0%), with 1-yr OS for PTCL-TFH at 88.9% (95%CI of 68.4%-100.0%). Mutational status by NGS was determined in 15 patients to date. The frequencies of the TET2, RHOA,DNMT3A, and IDH2 mutations were 73%, 40%, 13% and 13%, respectively. TET2 mutations were significantly associated with CR (p=0.014), favorable PFS (p-0.012) and OS (p=0.042). In contrast, DNMT3A mutations were associated with adverse OS (p=0.028). CONCLUSIONS: This study provides the first demonstration that addition of hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is feasible, safe, and induces high CR rate in PTCL-TFH subtype, with expected side effects. Although preliminary, the EOT CR to date exceeds the threshold of meeting study primary endpoint. Final efficacy data as well as response according to subtype and mutational profiling will be updated at ASH. This active combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL. Disclosures Ruan: Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy. Moskowitz:Seattle Genetics: Research Funding; Incyte: Research Funding; Merck: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; Genetech: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees. Horwitz:Portola: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Beigene: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy. Rutherford:LAM Therapeutics: Research Funding; Juno: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Genentech/Roche: Research Funding; Regeneron: Research Funding; Celgene: Consultancy; Heron: Consultancy; Karyopharm: Consultancy, Research Funding; Dova: Consultancy; Kite: Consultancy. Coleman:Novartis Pharmaceuticals: Research Funding; Innocare: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Ipsen Group: Research Funding; BMS (Celgene Corporation): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; Incyte Corporation: Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding; Boston BIoMedical, Inc.: Research Funding. Melnick:Jubilant: Consultancy; Epizyme: Consultancy; Constellation: Consultancy; Janssen: Research Funding; Daiichi Sankyo: Research Funding. Cerchietti:BMS: Research Funding. Leonard:ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; Regeneron: Consultancy; Sutro: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy; BMS/Celgene: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy. Martin:Regeneron: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Oral azacitidine (CC-486) as hypomethylating agent for the treatment of peripheral T-cell lymphoma

Beschreibung: Introduction: Patients (pts) with aggressive B-cell lymphomas who are relapsed or refractory to frontline therapy are typically treated with regimens including R-ICE (rituximab, ifosfamide, carboplatin, etoposide) followed by autologous stem cell transplant (ASCT) in responding pts. A minority of pts are cured with this approach, and the majority have poor outcomes. Selinexor is an oral, selective inhibitor of nuclear export, which activates tumor suppressor proteins and blocks translation of proteins that can contribute to chemoresistance, including MYC and BCL2. We conducted a phase I trial of selinexor plus R-ICE in pts with relapsed/refractory aggressive B-cell lymphomas. Methods: This phase I study used a 3+3 design with dose expansion. Eligible pts had diffuse large B-cell lymphoma (DLBCL), double hit lymphoma (DHL), and indolent lymphoma transformed to DLBCL. Treatment with 1 prior regimen administered with curative intent was required. Central nervous system (CNS) involvement was excluded. A separate cohort enrolled pts with Richter's transformation (RT) from chronic lymphocytic leukemia; there was no requirement with regard to prior therapies for this group. Selinexor was initially dosed at 40 mg (DL-1), 60 mg (DL1) and 80 mg (DL2) on days (d) -5, -3, 1, 3, and 5 and R-ICE on d1-3 of a 21-d cycle. Because of CNS toxicity thought to be primarily related to ifosfamide, the protocol was amended so that R-ICE was given on d1-3 and selinexor following completion of ifosfamide on d3, 5, and 7 of each cycle. After 2 cycles, responding pts were eligible to receive SCT or chimeric antigen receptor (CAR) T-cell therapy at discretion of treating physician. Dose limiting toxicity (DLT) period was cycle 1 and included grade (gr) 4 febrile neutropenia; gr 4 neutrophils for ≥7d; gr 4 platelets for ≥10d; gr 3 nausea, vomiting, diarrhea, or fatigue lasting 〉3d; or gr ≥3 non-hematologic toxicities except alopecia, fatigue or electrolyte abnormalities correctable with supportive care. Results: 22 pts enrolled with median age 67 (range 34-79). 64% were male and 36% female. Stage was III-IV in 72%. IPI was intermediate to high risk in 77%. Diagnosis was DLBCL NOS in 12, DHL in 4, transformed indolent lymphoma in 2, primary mediastinal large B-cell lymphoma in 1, and RT in 3. 7 pts were treated on the initial dosing schedule. In the first group at DL1, 0/3 pts had DLT. At DL2, 2/2 pts had DLT (gr 3 altered mental status, AMS). In the second group at DL1, 1/2 pts had DLT (gr 3 AMS). The dosing schedule was then modified as noted above. 12 DLBCL pts were treated on the modified dosing schedule. At DL1, 2/3 pts had DLT (gr 5 sepsis, gr 4 platelets ≥10d). At DL-1, 1/6 pts had DLT (gr 3 abdominal infection). Selinexor 40 mg was declared the recommended phase 2 dose (RP2D) and 3 pts were enrolled in an expansion. 3 pts with RT were treated on the modified dosing schedule; 2 received selinexor and neither had DLT at DL1. Median number of cycles of selinexor plus R-ICE was 2 (range 1-3). Most common gr 3-4 toxicities were cytopenias and hyponatremia. Most common non-hematologic toxicities of all grades were hyponatremia, fatigue, transaminitis, and nausea. Of 21 pts who received selinexor plus R-ICE, objective response rate (ORR) was 71% with 7 complete responses (CR), 8 partial responses (PR), and 3 stable disease (SD). 5 underwent SCT (3 autologous, 2 allogeneic) and 8 received CAR T-cells. Those who underwent transplant have not required additional therapy to date. 4 complete responders did not receive ASCT in part related to difficulty mobilizing stem cells; 3 have not required additional therapy with follow up of 26, 46, and 46 months. At the RP2D in the DLBCL cohort (n=9), ORR was 78% with 4 CR, 3 PR, and 2 SD. Conclusions: We report the first data on the combination of selinexor, which is now FDA-approved as a single agent in relapsed/refractory DLBCL, and chemotherapy in pts with aggressive B-cell lymphomas. We identified a dosing schedule of selinexor with R-ICE (40 mg on d3, 5, and 7) that is worthy of further study based on initial efficacy, with attention to CNS toxicity and impact on stem cell collection. Disclosures Rutherford: Karyopharm: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy; LAM Therapeutics: Research Funding; Kite: Consultancy; Juno: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Dova: Consultancy; Genentech/Roche: Research Funding; Heron: Consultancy. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Ruan:Celgene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Kite Pharma: Consultancy; Juno: Consultancy; BMS: Consultancy, Research Funding. Furman:Oncotarget: Consultancy; Loxo Oncology: Consultancy; Verastem: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy. Cerchietti:BMS: Research Funding. Gergis:Incyte: Speakers Bureau; Merck: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Mesoblast: Other: Ad Board; Jazz: Other: Ad board, Speakers Bureau. Leonard:Regeneron: Consultancy; BMS/Celgene: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; MEI Pharma: Consultancy; Sutro: Consultancy; Miltenyi: Consultancy. Martin:Bayer: Consultancy; Beigene: Consultancy; Kite: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Sandoz: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; I-MAB: Consultancy.