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Abstract Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020). Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge. Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed. Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant. Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo. Figure 1 Figure 1. Disclosures Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS

Abstract Background: Pts with previously treated R/R aggressive LBCL have compromised health-related QOL (HRQOL). Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In a prespecified interim analysis of TRANSFORM (NCT03575351), a randomized, open-label, pivotal trial, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and key secondary endpoints (complete response rate and progression-free survival) in adults with R/R LBCL after failure of first-line (1L) immunochemotherapy compared with SOC, with no new safety signals. Here we present results of the pt-reported outcomes (PRO) analysis from TRANSFORM. Methods: Adults (age ≤ 75 yrs) with R/R LBCL (≤ 12 mo after 1L therapy), who were eligible for autologous stem cell transplantation (ASCT), were randomized to receive either SOC (3 cycles of salvage chemotherapy [CT] and BEAM + ASCT for responding pts) or liso-cel after lymphodepletion. Crossover to receive liso-cel was allowed in the SOC arm for pts who failed treatment. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) were administered at randomization (baseline) and on Days 29 (infusion of liso-cel or 2 cycles of salvage CT), 64 (1 mo post liso-cel or completion of CT), 126 (3 mos post liso-cel or 2 mos post ASCT), and Mo 6 and other prespecified timepoints up to Mo 36 or end of study. No PRO data were collected after crossover. The analysis was based on the PRO-evaluable population (pts with a baseline and ≥ 1 post-baseline assessment). Predefined thresholds determined clinically meaningful changes. Global health/QOL (GH/QOL), physical functioning, cognitive functioning, fatigue, pain, and FACT-LymS were the primary domains of interest based on their relevance to the study population and treatment. A linear mixed model for repeated measures (MMRM) analysis was performed to assess the between-treatment difference in overall least squares (LS) mean change from baseline for each primary domain, using data collected up to Day 126 for visits with a sample size per arm ≥ 10. Proportions of pts with meaningful change from baseline were assessed for each primary domain up to Mo 6. All analyses were descriptive only. Results: Of 184 randomized pts, 90 (49%) and 85 (46%), respectively, were included in the PRO-evaluable population for the EORTC QLQ-C30 (SOC vs liso-cel n=43 vs 47) and FACT-LymS (n=40 vs 45, respectively). The PRO assessment completion rate from baseline up to Mo 6 was ≥ 45%, which was lower than expected primarily due to operational challenges during the COVID-19 pandemic but was comparable for both arms. In the MMRM analysis, the liso-cel arm had more favorable overall LS mean changes from baseline to Day 126 than the SOC arm in most of the EORTC QLQ-C30 domains and FACT-LymS. In particular, the between-treatment differences for cognitive functioning (−2.09 vs 2.21) and fatigue (3.75 vs −1.95) for SOC versus liso-cel, respectively, exceeded the prespecified minimal important difference threshold (Table); in those domains, the SOC arm deteriorated while the liso-cel arm improved. In individual-level analyses, the proportion of pts with meaningful improvement for fatigue and GH/QOL was higher, while deterioration was lower, in the liso-cel arm versus SOC arm from baseline up to Mo 6 (Figure). At Mo 6, a higher proportion of pts experienced worsened fatigue (71% vs 18%) and a lower proportion experienced improved fatigue (29% vs 47%) in the SOC arm compared with the liso-cel arm; for GH/QOL, a higher proportion of pts worsened (57% vs 18%) and lower proportion improved (14% vs 53%), respectively. For the other primary domains, the proportions of pts with improvement or deterioration favored liso-cel or were similar between arms. Conclusions: Compared with SOC, liso-cel showed favorable improvement in most primary PRO domains, particularly EORTC QLQ-C30 cognitive functioning and fatigue and more pts showed PRO improvements and fewer showed deterioration by Mo 6 with liso-cel. The results were achieved despite only responders remaining in the SOC arm after salvage CT. HRQOL was either improved or maintained after liso-cel treatment in pts with R/R LBCL after failure of 1L therapy. Figure 1 Figure 1. Disclosures Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Kite Pharma: Consultancy; Kymera: Consultancy; Incyte Corporation: Consultancy; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; BeiGene: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman: BMS: Current Employment, Current equity holder in publicly-traded company. Guo: Daiichi Sankyo: Consultancy; UCB: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bristol Myers Squibb: Consultancy; EMD Serono: Consultancy; Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Kamdar: ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; SeaGen: Speakers Bureau; Celgene: Other; Genetech: Other; Celgene (BMS): Consultancy.

Abstract The human RecQ helicase BLM is involved in the DNA damage response, DNA metabolism, and genetic stability. Loss of function mutations in BLM cause the genetic instability/cancer predisposition syndrome Bloom syndrome. However, the molecular mechanism underlying the regulation of BLM in cancers remains largely elusive. Here, we demonstrate that the deubiquitinating enzyme USP37 interacts with BLM and that USP37 deubiquitinates and stabilizes BLM, thereby sustaining the DNA damage response (DDR). Mechanistically, DNA double-strand breaks (DSB) promotes ATM phosphorylation of USP37 and enhances the binding between USP37 and BLM. Moreover, knockdown of USP37 increases BLM polyubiquitination, accelerates its proteolysis, and impairs its function in DNA damage response. This leads to enhanced DNA damage and sensitizes breast cancer cells to DNA-damaging agents in both cell culture and in vivo mouse models. Collectively, our results establish a novel molecular mechanism for the USP37–BLM axis in regulating DSB repair with an important role in chemotherapy and radiotherapy response in human cancers.

Abstract Standard treatment of catheter-associated upper extremity deep vein thrombosis (UE-DVT) is anticoagulation, although catheters are often removed for this indication. The optimal time for catheter removal and whether the act and/or timing of catheter removal is associated with pulmonary embolism (PE) remain unknown. A retrospective cohort study was performed at 8 participating institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies and central venous catheter (CVC)–associated UE-DVT were included from 1 January 2010 through 31 December 2016. The primary outcome was objectively confirmed PE within 7 days of UE-DVT diagnosis in anticoagulated patients comparing early (≤48 hours) vs delayed (>48 hours) catheter removal. A total of 626 patients were included, among whom 480 were treated with anticoagulation. Among anticoagulated patients, 255 underwent early CVC removal, while 225 had delayed or no CVC removal; 146 patients received no anticoagulation, among whom 116 underwent CVC removal alone. PE within 7 days occurred in 2 patients (0.78%) with early removal compared with 1 patient (0.44%) with delayed or no CVC removal (P > .9). PE or any cause of death within 7 days occurred in 3 patients in both the early removal (1.18%) and delayed/no removal (1.33%) groups (P > .9). In patients treated with CVC removal only (no anticoagulation), there were no PEs but 3 deaths within 7 days. In patients with hematological malignancy and CVC-associated UE-DVT, early removal of CVCs was not associated with an increased risk of PE compared with delayed or no removal.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Characterization of the recurrent genetic alterations in PDAC will yield improved understanding and therapies for this disease. Here, we report that PDAC patients with elevated expression of METTL16, one of the “writers” of RNA N6-methyladenosine (m6A) modification, may benefits from poly (ADP-ribose) polymerase (PARP) inhibitor treatment. Mechanistically, METTL16 interacts with MRE11 in an RNA-dependent manner; and, this interaction inhibits MRE11’s exonuclease activity in a methyltransferase-independent manner, thereby repressing DNA end resection. Upon DNA damage, ATM phosphorylates METTL16 at Ser419 within its C terminus, resulting in METTL16 conformational change and autoinhibition of its RNA binding. This dissociates the METTL16-RNA-MRE11 complex and releases inhibition of MRE11. Concordantly, PDAC cells with high METTL16 expression levels show increased sensitivity to PARP inhibitors, especially when combined with gemcitabine. Thus, our findings have revealed a role for METTL16 in homologous recombination repair and suggest that combination of PARP inhibitors with gemcitabine could be an effective treatment strategy for PDAC patients with high METTL16 expression.

Fibroblasts actively respond to changes in extracellular matrix mechanical properties, and positive feedback between matrix stiffness and fibroblast activation may play a pivotal role in fibrosis. Microarray analysis of matrix‐stiffness regulated genes in human lung fibroblasts identified significant overrepresentation of transcriptional targets of YAP (yes‐associated protein) and TAZ (transcriptional coactivator with PDZ‐binding motif), consistent with a prominent role for these factors in fibroblast mechanoresponsiveness. Immunofluorescence imaging demonstrated that YAP and TAZ transitioned from primarily nuclear localization on relatively stiff matrices (25.6 kPa) to cytoplasmic on soft matrices (0.4 kPa). RNAi‐mediated knockdown of YAP/TAZ significantly reduced the cell spreading, focal adhesion length, traction forces, proliferation, pro‐fibrotic gene expression and collagen synthesis observed on stiff matrices, but exerted negligible effects on soft matrices. Conditional overexpression of YAP overcame soft matrix limitations on proliferation, while overexpression of either YAP or TAZ promoted pro‐fibrotic gene expression on both soft and stiff matrices. Taken together, these results support a central role for YAP and TAZ in matrix stiffness‐dependent activation of fibroblasts to a proliferative, contractile and matrix synthetic state implicated in the pathogenesis of fibrosis. Grant Funding Source : Supported by NIH RO1 HL092961

Abstract Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. Significance: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistant-related MET amplification. This article is highlighted in the In This Issue feature, p. 2659

As a member of the phylum Cnidaria, the body wall of hydra is organized as an epithelium bilayer (ectoderm and endoderm) with an intervening extracellular matrix (ECM). Previous studies have established the general molecular structure of hydra ECM and indicate that it is organized as two subepithelial zones that contain basement membrane components such as laminin and a central fibrous zone that contains interstitial matrix components such as a unique type I fibrillar collagen. Because of its simple structure and high regenerative capacity, hydra has been used as a developmental model to study cell-ECM interaction during epithelial morphogenesis. The current study extends previous studies by focusing on the relationship of ECM biogenesis to epithelial morphogenesis in hydra, as monitored during head regeneration or after simple incision of the epithelium. Histological studies indicated that decapitation or incision of the body column resulted in an immediate retraction of the ECM at the wound site followed by a re-fusion of the bilayer within 1 hour. After changes in the morphology of epithelial cells at the regenerating pole, initiation of de novo biogenesis of an ECM began within hours while full reformation of the mature matrix required approximately 2 days. These processes were monitored using probes to three matrix or matrix-associated components: basement membrane-associated hydra laminin β1 chain (HLM-β1), interstitial matrix-associated hydra fibrillar collagen (Hcol-I) and hydra matrix metalloproteinase (HMMP). While upregulation of mRNA for both HLM-β1 and Hcol-I occurred by 3 hours, expression of the former was restricted to the endoderm and expression of the latter was restricted to the ectoderm. Upregulation of HMMP mRNA was also associated with the endoderm and its expression paralleled that for HLM-β1. As monitored by immunofluorescence, HLM-β1 protein first appeared in each of the two subepithelial zones (basal lamina) at about 7 hours, while Hcol-I protein was first observed in the central fibrous zone (interstitial matrix) between 15 and 24 hours. The same temporal and spatial expression pattern for these matrix and matrix-associated components was observed during incision of the body column, thus indicating that these processes are a common feature of the epithelium in hydra. The correlation of loss of the ECM, cell shape changes and subsequent de novo biogenesis of matrix and matrix-associated components were all functionally coupled by antisense experiments in which translation of HLM-β1 and HMMP was blocked and head regeneration was reversibly inhibited. In addition, inhibition of translation of HLM-β1 caused an inhibition in the appearance of Hcol-I into the ECM, thus suggesting that binding of HLM-β1 to the basal plasma membrane of ectodermal cells signaled the subsequent discharge of Hcol-I from this cell layer into the newly forming matrix. Given the early divergence of hydra, these studies point to the fundamental importance of cell-ECM interactions during epithelial morphogenesis.