Innate Pharma Research Articles

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study

Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Treatment Outcomes of Consolidative Radiation in Extranodal Early-Stage Diffuse Large B-Cell Lymphoma

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma, with approximately 25-30% of patients presenting as early or limited-stage (stage I and II). Though treatment with chemoimmunotherapy is standard of care, the role of consolidative radiotherapy (RT) in limited-stage (LS) patients is not well defined. Recent studies have attempted to shorten chemotherapy courses and eliminate RT for LS patients. Additionally, recent single institutional data has suggested LS patients with extranodal (EN) disease may have better outcomes if treated with RT. We aimed to investigate whether the addition of RT provided a survival benefit in early-stage DLBCL patients based on primary site at presentation comparing nodal to EN disease.MethodsThe National Cancer Database was utilized to identify patients diagnosed with LS-DLBCL from 2004 to 2015. Only patients treated with multiagent chemotherapy were included. Patients with international prognostic index (IPI) score available were separated into low (0-1 factors) or high-risk (2-4) groups. Landmark analysis was performed to exclude patients with last contact, including death, within 12 months of diagnosis. Kaplan-Meier survival analysis was used to compare overall survival (OS). Cox regression analysis was used to identify hazard ratios for survival using RT between subgroups.ResultsOf the 39,745 LS patients identified, 62.9% had nodal disease and 37.1% had EN disease with stage I disease accounting for 51.5% of patients. Only 6,628 patients had reported IPI scores with the majority having low-risk IPI (69.2%). Compared to patients with only nodal disease, patients with EN involvement were more likely to receive consolidative RT (42.9% vs 37.2%; p<0.05). EN patients were most likely to receive RT with primary bone (67.7% of 1526 patients), skin/soft tissue (60.3% of 1353), breast (58.6% of 652), testes (58.4% of 950) and thyroid (56.6% of 1059) involvement (all p<0.05). GI (18.1% of 4652) and lung (23.3% of 614) primaries were least likely to receive RT (p<0.05). With a median follow up of 58.8 months, the addition of RT was associated with improved 5-year OS for all LS patients as compared to those treated with chemotherapy alone (68 vs. 62%, p<0.001). While RT was associated with improved 5-year OS in both the nodal and EN disease patients, nodal patients had a greater benefit of receiving RT as compared to EN patients (nodal: 71% vs. 63%, p<0.001; EN: 64% vs. 62%; p<0.001). Specifically, in EN patients, the addition of RT significantly increased 5-year OS for skin/soft tissue (60% vs. 57%, p<.001), head and neck (63% vs. 60%, p<0.02), testicular (63% vs. 45%, p<.001), and thyroid sites (73% vs. 67%, p <0.02). Furthermore, RT slightly improved 5-year OS outcomes for patients with both low-risk (75% vs. 73%; p<0.01) and high-risk IPI (52% vs. 50%; p<0.04). On multivariate analysis, adjusting for age, stage, and Charlson-Deyo comorbidity score, the addition of RT was an independent factor for improved survival for all LS patients (Hazard Ratio [HR] 0.84, 95% Confidence Interval [CI] 0.81-0.88; p<0.001) along with EN sites of skin/soft tissue (HR 0.72, 95% CI 0.58-0.88; p<0.01), testicle (HR 0.70, 95% CI 0.54-0.90, p<0.01) and thyroid (HR 0.68, 95% CI 0.51-0.90; p<0.01). No significant survival differences were observed in patients with EN involvement of the lung, bone, breast, or GI tract when RT was added to their treatment.ConclusionsWe report the largest retrospective study on EN outcomes utilizing consolidative RT in early-stage DLBCL. Though there is no consensus on optimal treatment indications for RT in LS-DLBCL, this data shows improved OS in both nodal only disease and within specific EN disease subgroups when RT is added to front-line chemotherapy. As recent studies have attempted to shorten chemotherapy cycles and limit the use of RT, these results suggest caution against omission of RT in select patients. [Display omitted] DisclosuresShah: AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Epizyme: Research Funding. Stephens: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Abbvie: Consultancy; JUNO: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

Maximal Tolerated Dose Determined for Venetoclax in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory Ph-Negative T-Cell or B-Cell Acute Lymphoblastic Leukemia: Results of Phase 1 Portion of ECOG-ACRIN EA9152

Chromatin Accessibility Profiling to Increase Diagnostic Accuracy and Refine Cell-of-Origin Classification of Mature T-Cell Lymphomas

Background:Mature T-cell lymphomas and leukemias (MTCL) are heterogeneous diseases with dismal prognosis. Differentiating between the numerous entities requires specialized pathology expertise and studies show up to 20% change in diagnosis after expert review of cases (Laurent, JCO, 2017). Assay for transposase accessible chromatin sequencing (ATAC-seq) is a simple technique to profile open chromatin regions (OCR) proven to be highly discriminant for cell-of-origin identification regardless of cell activation status (Shih, Cell, 2016). We applied ATAC-seq to MTCL in order to explore the epigenetic landscape of these diverse entities, compared them to normal T-cell subtypes and built a predictive model to help diagnosis.Method:Ten-thousand FACS-sorted single cells from primary MTCL samples and 50µm section of frozen tumoral tissue from the TENOMIC French T-cell Lymphoma Consortium were processed according to the previously published FAST-ATAC and OMNI-ATAC protocols respectively (Corces, Nat Genetics, 2016 & Nat. Methods, 2017). Concurrently we applied FAST ATAC to different normal T- and NK-cell subsets sorted from healthy donor PBMC or lymph node suspensions. Sequencing data were processed by an adapted version of ENCODE ATAC-seq pipeline. Matrix of insertion events in peaks by sample was obtained, normalized and most variant peaks were selected for UMAP projection.Results:In total, 678 normal and tumoral samples were sequenced to provide a comprehensive landscape of chromatin accessibility in MTCL. Epigenetic profiling by ATAC-seq of FACS-sorted tumoral samples resulted in a complete segregation of the known MTCL entities (AITL, TFH-PTCL, ALK+ and ALK- ALCL, HSTL, CTCL, ATLL, LGL and T-PLL). Most PTCL-NOS (13/17) clustered with a pre-defined MTCL subtype (mainly AITL/TFH-phenotype PTCL, CTCL and lymphomas exhibiting cytotoxic features). All but one discordant diagnosis between pathology and ATAC-seq (1/11) led to revised diagnosis after pathology review.Unsupervised clustering of normal NK- and T-cell subtypes (N=49) and sorted tumoral lymphoma cells (N=104) confirmed that AITL derive from TFH cells. HSTL and LGL closely segregated with NK- and gamma-delta T cells, in line with their known innate-like phenotype.Surprisingly, the cell-of-origin of T-PLL seems to be naïve T cells despite the known expression of central memory markers on leukemic cells.Beyond epigenetic classification, background reads from ATAC-seq profiles were used to detect copy number variation (CNV), such as isochromosome 7q in HSTL. In addition, HTLV1 and EBV viral sequence detection in ATAC-seq reads strengthened identification of ATLL and NKTCL cases.Finally, using unsupervised deconvolution approaches, we were able to discriminate different MTCL subtypes from 223 processed bulk frozen samples. All known MTCL subtypes were differentiated (AITL/PTCL-TFH, HSTL, NKTCL, ATLL, ALK- and ALK+ ALCL, MEITL, EATL). A subgroup of PTCL-NOS harboring GATA3 OCRs and a distinctly high CNV number was isolated that might correspond to previously described PTCL-GATA3 subtypes (Iqbal, Blood, 2019).A random forest model was trained to predict diagnosis based on chromatin-accessibility clusters defined in the discovery cohort of patients. The model showed accurate prediction performance by cross-validation. External validation on 172 samples collected from 5 tertiary care centers will be presented at the meeting.Conclusion:ATAC-seq is a fast and cost-effective technique to help and refine MTCL pathological classification and allows for putative cell-of-origin identification in lymphoma. Training of a machine learning model to predict MTCL entity diagnosis based on ATAC-seq analysis of fresh or frozen samples shows promising results. [Display omitted] DisclosuresSibon: Janssen: Consultancy; Abbvie: Consultancy; iQone: Consultancy; Takeda: Consultancy; Roche: Consultancy. Drieux: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties.. Ruminy: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. . Salles: Takeda: Consultancy; Velosbio: Consultancy; Ipsen: Consultancy; Allogene: Consultancy; Miltneiy: Consultancy; Genentech/Roche: Consultancy; Genmab: Consultancy; Janssen: Consultancy; Loxo: Consultancy; Kite/Gilead: Consultancy; Regeneron: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; Incyte: Consultancy; Rapt: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Gaulard: Alderaan: Research Funding; Sanofi: Research Funding; Innate Pharma: Research Funding; Gilead: Consultancy; Takeda: Consultancy, Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy.

Safety of Anti-NKG2A Blocking Antibody Monalizumab As Maintenance Therapy after Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I Study

BackgroundFollowing allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the phenotype and function of circulating NK Cells are altered; notably NK cells display an immature (CD56-bright/KIR -/CD57 -/NKG2A +) phenotype and a low cytotoxic activity. Since NK cells have demonstrated anti-leukemic activity in the context of Allo-HCT while less prone to induce GVHD than T cells, we hypothesized that NKG2A inhibition using the checkpoint inhibitor monalizumab (humanized IgG4 blocking monoclonal antibody) could improve NK cell mediated graft-versus-tumor effect, without triggering graft-versus-host disease. We thus performed the first clinical trial evaluating the safety of monalizumab as a prophylactic treatment after Allo-HSCT (NCT02921685).MethodThe objective was to determine the maximal tolerated dose (MTD) of a single infusion of monalizumab administered on day+75 or thereafter following Allo-HSCT. Inclusion criteria were: 1) adult patients who underwent first Allo-HSCT for hematological malignancy; 2) no prior history of GVHD, 3) reduced toxicity conditioning regimen, 4) ATG or PT-Cy based GVHD prophylaxis, and 5) GVHD prophylaxis with cyclosporine A ongoing at the time of monalizumab infusion.Four dose levels were investigated in this dose escalation study (0.04, 0.1, 0.3, and 1.0 mg/kg). Dose limiting toxicities (DLT) were defined by the occurrence of any grade 3 to 4 monalizumab-related adverse event within 28 days after infusion, including grade 3 to 4 acute GVHD and moderate to severe chronic GVHD. In case of DLT, a Bayesian continuous reassessment model (CRM) was used to predict the maximal tolerated dose (MTD) after each series of 3 patients treated at a given dose level. It was planned to treat 18 patients. Beyond clinical safety, blood samples were collected for NK and T cell immunomonitoring and receptor saturation assay.ResultsFifteen patients received monalizumab at a median time of 83 days (range: 75-103) after Allo-HSCT (3 at 0.04 mg/kg, 3 at 0.1 mg/kg, 3 at 0.3 mg/kg, and 6 at 1 mg/kg). Patients were transplanted for hematological diseases (9 AML, 3 MDS, 1 lymphoma, 1 CLL and 1 myelofibrosis), from a matched sibling (n=8), matched unrelated (n=6) or haploidentical donor (n=1).No DLT was observed during the dose escalation process or among the 6 patients treated at the highest dose level, justifying study early termination after 15 patients. Two patients developed transient low grade GVHD that spontaneously resolved without treatment (1 grade I acute GVHD on day+8 and 1 mild chronic GVHD on day+118). Systemic steroid requiring GVHD occurred in 3 patients (20%): 1 severe overlap GVHD (day+42, CR after treatment), 1 severe chronic GVHD (day+80, death from GVHD) and 1 late severe chronic GVHD after cyclosporine tapering for mixed chimerism (day+149, complete remission [CR] after treatment). No disease recurrence was observed, except for one patient with myelofibrosis who relapsed 3 years after monalizumab infusion. At a median follow up of 22 months (3-48) after monalizumab infusion, 13 out of 15 patients are in CR from their underlining malignancy without GVHD and immunosuppressive treatment at last contact.At the dose of 1 mg/kg, receptor saturation assays (RSA) showed persistent binding of monalizumab on peripheral blood NK cells. Indeed, more than 90% of NKG2A-positive NK cells were positive for monalizumab detection (Anti-IgG4-PE) until at least 14 weeks post treatment.ConclusionsMonalizumab can be safely administered after Allo-HSCT, with prolonged persistence on circulating NK cells. In the absence of DLT, MTD was not reached. Future trials will aim at measuring the clinical efficacy of monalizumab in this context, alone or in combination therapy. Disclosuresboyer Chammard: Innate Pharma: Current Employment. Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Olive: ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

The Intestinal Microbiota Correlates with Response and Toxicity after CAR T Cell Therapy in Patients with B-Cell Malignancies

The Intestinal Microbiota Correlates with Response and Toxicity after CAR T Cell Therapy in Patients with B-Cell Malignancies

"IF-Better" Gating: Combinatorial Targeting and Synergistic Signaling for Enhanced CAR T Cell Efficacy

Abstract CAR T cell therapy provides a potent therapeutic option in various B cell-related hematologic malignancies. One of the major efficacy challenges is escape of tumor cells with low antigen density, which has been clinically observed in several malignancies treated with CAR therapy. Novel concepts of CAR design are needed to address phenotypic heterogeneity including clonal variability of target antigen expression. In the study presented here, we focused on AML and selected ADGRE2 as CAR target due to its high rate of positivity on AML bulk and leukemic stem cells (LSC) in a molecularly heterogeneous AML patient population. We chose an ADGRE2-CAR with optimized scFv affinity and fine-tuned CD3zeta signaling to achieve an ideal killing threshold that would allow for sparing of ADGRE2-low normal cells. We hypothesized that co-targeting of a second AML-related antigen may mitigate potential CAR target antigen-low AML escape and we identified CLEC12A as preferential co-target due to its non-overlapping expression profiles in normal hematopoiesis and other vital tissues. We developed ADCLEC.syn1, a novel combinatorial CAR construct consisting of an ADGRE2-targeting 28z1XX-CAR and a CLEC12A-targeting chimeric costimulatory receptor (CCR). ADCLEC.syn1 operates based on what we describe as "IF-BETTER" gate: High CAR target expression alone triggers killing, whereas low CAR target expression does not, unless a CCR target is present. Additional CCR interaction lowers the threshold for CAR-mediated killing through increased avidity and costimulation, allowing for higher CAR sensitivity that is purposefully limited to target cells expressing both antigens. In the context of ADCLEC.syn1, ADGRE2-high/CLEC12A-negative AML cells can trigger cell lysis while ADGRE2-low/CLEC12A-negative normal cells are spared. Importantly, ADGRE2-low/CLEC12A-high AML cells are also potently eliminated, preventing ADGRE2-low AML escape. Using NSG in-vivo xenograft models of engineered MOLM13 AML cell line variants with low levels of ADGRE2 to model antigen escape, we found that ADCLEC.syn1 outperforms a single-ADGRE2-CAR lacking assistance via CLEC12A-CCR. Importantly, ADCLEC.syn1 also outperformed an otherwise identical alternative dual-CAR version (OR-gated ADGRE2-CAR+CLEC12A-CAR) in the setting of both ADGRE2-high and ADGRE2-low MOLM13, further underlining the importance of fine-tuned overall signaling. We confirmed high in-vivo potency against diverse AML cell lines with a wide range of ADGRE2 and CLEC12A levels reflecting population-wide AML heterogeneity. At clinically relevant CAR T cell doses, ADCLEC.syn1 induced complete and durable remissions in xenograft models of MOLM13 (ADGRE2-high/CLEC12A-low) and U937 (ADGRE2-low/CLEC12A-high). ADCLEC.syn1 CAR T cells were found to be functionally persistent for &amp;gt;70 days, with a single CAR T cell dose potently averting relapse modeled via AML re-challenges. In summary, we provide pre-clinical evidence that an "IF-BETTER"-gated CAR+CCR T cell (ADCLEC.syn1) can outperform a single-CAR T cell (ADGRE2-CAR) and a dual-CAR T cell (ADGRE2-CAR+CLEC12A-CAR). ADCLEC.syn1 enhances antileukemic efficacy and prevents antigen-low AML escape via detection of a rationally selected combinatorial target antigen signature that is commonly found in AML but limited in vital normal cells. Using phenotypically representative AML xenograft models and clinically relevant T cell doses, we demonstrate high therapeutic potential of ADCLEC.syn1 CAR T cells, further supporting clinical translation of an "IF-BETTER"-gated CAR concept into a phase 1 trial. Disclosures Haubner: Takeda Pharmaceuticals Company Ltd.: Patents &amp; Royalties: Co-inventor of IP that MSK licensed to Takeda, Research Funding. Mansilla-Soto: Takeda Pharmaceuticals Company Ltd.: Patents &amp; Royalties; Atara Biotherapeutics: Patents &amp; Royalties; Fate Therapeutics: Patents &amp; Royalties; Mnemo Therapeutics: Patents &amp; Royalties. He: Takeda Pharmaceuticals Company Ltd.: Ended employment in the past 24 months, Patents &amp; Royalties. Park: Curocel: Consultancy; BMS: Consultancy; Innate Pharma: Consultancy; Autolus: Consultancy; Servier: Consultancy; Kite Pharma: Consultancy; Affyimmune: Consultancy; Intellia: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; Amgen: Consultancy; Kura Oncology: Consultancy; Artiva: Consultancy; Novartis: Consultancy. Rivière: Juno Therapeutics: Patents &amp; Royalties; Fate Therapeutics: Other: Provision of Services, Patents &amp; Royalties; Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); FloDesign Sonics: Other: Provision of Services. Sadelain: NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); St. Jude Children's Research Hospital: Other: Provision of Services; Minerva Biotechnologies: Patents &amp; Royalties; Mnemo Therapeutics: Patents &amp; Royalties; Juno Therapeutics: Patents &amp; Royalties; Fate Therapeutics: Other: Provision of Services (uncompensated), Patents &amp; Royalties; Ceramedix: Patents &amp; Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents &amp; Royalties; Atara Biotherapeutics: Patents &amp; Royalties.

A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

Safety and Efficacy of Third Generation CD20 Targeted CAR-T (MB-106) for Treatment of Relapsed/Refractory B-NHL and CLL

Safety and Efficacy of Third Generation CD20 Targeted CAR-T (MB-106) for Treatment of Relapsed/Refractory B-NHL and CLL

Safety and Efficacy of Ibrutinib Maintenance (I-M) Following Frontline Induction in Mantle Cell Lymphoma (MCL) with Sequential Assessment of Changes in NGS-MRD

Safety and Efficacy of Ibrutinib Maintenance (I-M) Following Frontline Induction in Mantle Cell Lymphoma (MCL) with Sequential Assessment of Changes in NGS-MRD

Evaluation of the Incidence and Risk Factors Associated with Bleeding Events in Patients Receiving Acalabrutinib Therapy

Background:Acalabrutinib is a more selective, second generation covalent binding Bruton tyrosine kinase (BTK) inhibitor. It was designed with the intent to mitigate adverse events (AEs) associated with ibrutinib, such as bleeding and cardiovascular events. In the phase 3 trial that that led to acalabrutinib approval in the front line setting for chronic lymphocytic leukemia (CLL), 37% and 2% of patients who received acalabrutinib monotherapy experienced grade 1-2 or ≥3 bleeding events, respectively. Currently, there are no long term studies evaluating the incidence of bleeding events associated with acalabrutinib. Therefore, the purpose of this study was to assess the incidence of bleeding events, and risk factors associated with bleeding events for patients treated with acalabrutinib for hematologic malignancies.Methods:This was a single center retrospective study conducted at The Ohio State University. Patients were included if they were ≥18 years old, diagnosed with a hematologic malignancy, and initiated on acalabrutinib (monotherapy or combination therapy) between January 1, 2010 and August 31, 2019. The International Society on Thrombosis and Haemostasis (ISTH) bleeding scale (no bleed, clinically non-relevant bleed, and clinically relevant/major bleed) and Common Terminology Criteria for Adverse Events V5.0 (CTCAE) were used to evaluate the grade and class of bleed events. Descriptive statistics were used to summarize demographic information and bleed events; univariable analysis was used to assess risk factors.Results:We analyzed 289 patients who received acalabrutinib for a hematologic malignancy. The main source of acalabrutinib was from clinical trials (85%) and the median acalabrutinib exposure time for all patients was 40.8 months (range: 0-81.6 months). 89% of patients had CLL, 2% had mantle cell lymphoma, and 9% had other non-Hodgkin's lymphoma. Additionally, 18% of patients had a prior bleed history and 51% were continued on concomitant medications that increase bleeding (Table 1). There were a total of 241 (83%) patients who experienced at least one bleed event. Per ISTH categorization, 143 (59%) patients' most severe bleed event was clinically non-relevant and 98 (41%) patients' was clinically relevant/major; cutaneous bleeds were most common in both groups, 71% and 31%, respectively. Only 6% of patients had a major bleed, hence, clinically relevant and major bleeds were analyzed together for the purpose of this study.There were a total of 633 bleed events that occurred in this study population; 76% were clinically-non relevant and only 3% (n=17) were CTCAE grade ≥3. Acalabrutinib was not discontinued or held for any clinically non-relevant bleeds, was discontinued for six (1%) clinically relevant/major bleeds, and held for 44 (7%) clinically relevant/major bleeds. Clinically relevant /major bleeds also resulted in discontinuations of concomitant anticoagulation and antiplatelet therapy in only 4% (n=24) of cases. 1263 procedures were identified and the incidence of clinically non-relevant and clinically relevant/major bleeds related to surgeries/procedures was 1% (n=12) and 1.3% (n=16), respectively.10% of clinically non-relevant and 57% of clinically relevant/major bleeds led to hospitalizations, emergency room visits, or physician office visits; including two major CNS bleed events which resulted in death. The overall survival (OS) was not reached in the clinically non-relevant and clinically relevant/major bleed groups and was 14 months (95% CI 6-40) in the no bleed group (p=0.021). Univariate analysis showed that risk factors associated with a clinically relevant/major bleed included concomitant medications (OR 3.06, 95% CI 1.49-6.26) and prior bleed history (OR 4.40, 95% CI 1.45-13.40) (Table 3).Conclusions:Overall, our study had a long acalabrutinib exposure time and demonstrated a low incidence of grade ≥3 bleeds. There was also a low risk of bleeds related to procedures. The majority of bleeds were clinically non-relevant that did not result in significant treatment adjustments, hospitalizations, or death. This study identified prior bleed history and concomitant medications that increase bleeding as risk factors for bleeds and should be evaluated prior to starting acalabrutinib therapy. Our data supports acalabrutinib as a safe long-term treatment in regards to bleeds for patients with hematologic malignancies. [Display omitted] DisclosuresWiczer: BTG Specialty Pharmaceuticals: Consultancy. Bhat: Beigene: Consultancy; Aptitude Health: Honoraria; AstraZeneca: Consultancy; Onclive: Honoraria. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Rogers: Janssen Pharmaceuticals, Inc: Research Funding; Pharmacyclics LLC: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Innate Pharma: Consultancy; ovartis Pharmaceuticals Corporation: Research Funding; AbbVie Inc.: Consultancy, Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

Impact of Molecular Features of Diffuse Large B-Cell Lymphoma on Treatment Outcomes with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Impact of Molecular Features of Diffuse Large B-Cell Lymphoma on Treatment Outcomes with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults

Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study

Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study

Oral Ixazomib in Untreated Follicular Lymphoma Permits COVID-19 Vaccine Response and Its Efficacy Is Associated with Clinical Factors and Gene Expression Signatures

Oral Ixazomib in Untreated Follicular Lymphoma Permits COVID-19 Vaccine Response and Its Efficacy Is Associated with Clinical Factors and Gene Expression Signatures

Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

Lesion Characteristics and Patterns of Failure in Diffuse Large B Cell Lymphoma Patients Treated with Bridging Radiotherapy Prior to Chimeric Antigen Receptor T Cell Therapy

Lesion Characteristics and Patterns of Failure in Diffuse Large B Cell Lymphoma Patients Treated with Bridging Radiotherapy Prior to Chimeric Antigen Receptor T Cell Therapy