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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.govas #NCT03050216 and #NCT01898793.

IMPORTANCE: In 2010, the US Centers for Medicare & Medicaid Services (CMS) indicated that data regarding efficacy of allogeneic hematopoietic stem cell transplantation (HCT) in the CMS beneficiary population with myelodysplastic syndrome (MDS) were currently insufficient, but that coverage would be provided for patients enrolled in a clinical study that met its criteria for Coverage with Evidence Development (CED). OBJECTIVE: The Center for International Bone Marrow Transplant Research (CIBMTR) submitted a study concept comparing the outcomes of patients aged 55 to 64 years vs aged 65 years or older who met those criteria, effectively providing coverage by CMS for HCT for MDS. DESIGN, SETTING, AND PARTICIPANTS: Data on patients aged 65 years or older were prospectively collected and their outcomes compared with patients aged 55 to 64 years. Patients were enrolled in the study from December 15, 2010, to May 14, 2014. The results reported herein were analyzed as of September 4, 2017, with a median follow-up of 47 months. The study was conducted by the CIBMTR. It comprises a voluntary working group of more than 420 centers worldwide that contribute detailed data on allogeneic and autologous HCT and cellular therapies. INTERVENTIONS: Patients with MDS received HCT according to institutional guidelines and preferences. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS); secondary outcomes included nonrelapse mortality (NRM), relapse-free survival, and acute and chronic graft vs host disease. RESULTS: During the study period, 688 patients aged 65 years or older underwent HCT for MDS and were compared with 592 patients aged 55 to 64 years. Other than age, there were no differences in patient and disease characteristics between the groups. On univariate analysis, the 3-year NRM rate was 28% vs 25% for the 65 years or older group vs those aged 55 to 64 years, respectively. The 3-year OS was 37% vs 42% for the 65 years or older group vs the 55 to 64 years age group, respectively. On multivariable analysis after adjusting for excess risk of mortality in the older group, age group had no significant association with OS (HR, 1.09; 95% CI, 0.94-1.27; P = .23) or NRM (HR, 1.19; 95% CI, 0.93-1.52; P = .16). CONCLUSIONS AND RELEVANCE: Older patients with MDS undergoing HCT have similar OS compared with younger patients. Based on current data, we would recommend coverage of HCT for MDS by the CMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01166009

Introduction: Clonal cytopenias of undetermined significance (CCUS) and myelodysplastic syndromes (MDS) represent a disease continuum that are distinguished by the presence of dysplasia in >10% of blood cells. However, morphologic dysplasia is subject to high inter-observer variability, suggesting that dysplasia may not be ideal to differentiate CCUS from MDS. Defining the clonal architecture of samples from cytopenic patients may provide a more accurate objective measure of disease status than dysplasia. We hypothesize that the number and size of subclones is reduced in patients with CCUS compared to MDS, suggesting that increased subclonal diversity is a hallmark of higher-risk disease.

Introduction:Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk myelodysplastic syndrome (HR MDS) compared to lower-intensity, conventional treatment regimens; however, improvement in clinical outcomes are needed. Clinical data on the synergy of Aza with venetoclax (Ven)-a selective, potent BCL-2 inhibitor-in the treatment of myeloid malignancies and the unmet need in HR MDS provide a rationale to evaluate Ven in combination with Aza in treatment-naive HR MDS. Here, we report efficacy and safety data in patients with treatment-naive HR MDS treated with Ven+Aza at the recommended Phase 2 dose (RP2D) in the safety expansion part of the Phase 1b study (NCT02942290).

Introduction:The standard of care for patients with high-risk myelodysplastic syndrome (HR-MDS) who are eligible for intensive therapy includes allogeneic stem cell transplantation (SCT), which is potentially curative. Venetoclax (Ven) is a potent, selective, orally bioavailable BCL-2 inhibitor, which has a synergistic effect when combined with hypomethylating agents in preclinical and clinical investigations of myeloid malignancies. Previous results showed that the combination of Ven and azacitidine (Aza) is associated with an acceptable safety profile and leads to rapid and durable responses in patients with treatment-naive HR-MDS. Here, we report the clinical outcomes of patients with HR-MDS who proceeded to SCT following combination Ven+Aza treatment on the M15-531 clinical trial.

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2(80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.govas #NCT01607892.

Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2(60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.govas #NCT01607892.

Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter’s transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.

•Early post-allo-HCT IV AZA starting on day +7 at 45mg/m2is overall well-tolerated•Post-transplant AZA has limited efficacy in preventing acute and chronic GvHD•This AZA schedule could have a beneficial effect in preventing disease relapse

Recent whole-genome sequencing (WGS) studies have demonstrated that tumors typically comprise a founding clone and multiple subclones (i.e., clonal heterogeneity is common). The possible combination of mutations in each tumor clone is enormous, making each tumor genetically unique. Clonal heterogeneity likely has a role in cancer progression, relapse, metastasis, and chemoresistance due to functional differences in genetically unique subclones. In current clinical practice, gene mutations are only classified as being present or absent, ignoring the clonal complexity of cancers. In this review, we address how tumor clonality is measured using next-generation sequencing (NGS) data, highlight that clonal heterogeneity is common across multiple tumor types, and discuss the potential clinical implications of tumor clonal heterogeneity.

Altered microRNA (miRNA) expression is frequently observed in acute myelogenous leukemia (AML) and has been implicated in leukemic transformation. Whether somatic copy number alterations (CNAs) are a frequent cause of altered miRNA gene expression is largely unknown. Herein, we used comparative genomic hybridization with a custom high-resolution miRNA-centric array and/or whole-genome sequence data to identify somatic CNAs involving miRNA genes in 113 cases of AML, including 50 cases of de novo AML, 18 cases of relapsed AML, 15 cases of secondary AML following myelodysplastic syndrome, and 30 cases of therapy-related AML. We identified a total of 48 somatic miRNA gene-containing CNAs that were not identified by routine cytogenetics in 20 patients (18%). All these CNAs also included one or more protein coding genes. We identified a single case with a hemizygous deletion of MIR223, resulting in the complete loss of miR-223 expression. Three other cases of AML were identified with very low to absent miR-223 expression, an miRNA gene known to play a key role in myelopoiesis. However, in these cases, no somatic genetic alteration of MIR223 was identified, suggesting epigenetic silencing. These data show that somatic CNAs specifically targeting miRNA genes are uncommon in AML.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Background: Previous studies indicate that mutations in signaling (e.g., receptor tyrosine kinases and RASpathway members) and transcription factor genes are more common in secondary acute myeloid leukemia (sAML) than myelodysplastic syndrome (MDS), suggesting a role in disease progression. However, our understanding of the timing and order of mutation acquisition in these genes remains incomplete without analyzing paired MDS and sAML samples from the same patient. Defining the role of signaling gene mutations during progression should provide biologic insight into clonal evolution and help define prognostic markers for MDS progression.

DiPersio: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Jacoby:AbbVie: Research Funding; Jazz Pharmaceuticals: Research Funding.

Background

Introduction: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are advanced myeloid neoplasms with poor survival and no curative therapy except allogeneic transplant; they are enriched for mutations in the spliceosome complex, including the genes SF3B1, SRSF2, ZRSR2,and U2AF1. Ceralasertib (AZD6738) is a selective and potent orally bioavailable inhibitor of Ataxia Telangiectasis and Rad3 Related (ATR) kinase. Expression of mutant spliceosome genes induces alternative splicing and R loops (DNA:RNA hybrids) in human hematopoietic cells. ATR is a critical mediator for R loop resolution; if ATR is inhibited, cells that have excess R loops undergo apoptosis, whereas normal cells are spared. We hypothesized that inhibition of ATR may be useful in patients with MDS or CMML, particularly those who harbor splicing factor gene mutations.

Introduction: CPX-351 (Vyxeos ©; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio that is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Secondary AML is clinically and biologically similar to MDS, sharing many of the same genetic mutations. We hypothesize that CPX-351 therapy may result in deeper responses than traditional therapy with hypomethylating agents, with acceptable tolerability, and translate into better outcomes in the MDS population. This is a multicenter, dose-escalation and safety expansion study (NCT03572764) to investigate induction and consolidation therapy with CPX-351 in a transplant eligible, higher risk MDS population.

Introduction:

Garcia: Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Prelude: Research Funding; Pfizer: Research Funding. Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Fong: Amgen, BMS: Speakers Bureau; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria; Amgen: Research Funding. Borate: Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cunningham: AbbVie, Amgen, Astex, Celgene, Janssen, Novartis, Principia Biopharma, Rigel: Research Funding. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Nowak: Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; AbbVie: Other: Investigator on funded clinical trial; Affimed: Research Funding; Tolero Pharma, Pharmaxis, Apogenix: Research Funding; Celgene: Honoraria; Takeda: Honoraria. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Dunshee: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Zhou: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Hoffman: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Sun: AbbVie: Current Employment. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ainsworth: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Kye: AbbVie: Current Employment, Other: May hold equity. Hogdal: AbbVie: Current Employment, Current holder of stock options in a privately-held company.

Brunner: Keros Therapeutics: Consultancy; AstraZeneca: Research Funding; GSK: Research Funding; Aprea: Research Funding; Agios: Consultancy; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Garcia: Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding. Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Dean: AstraZeneca: Current Employment. Smith: AstraZeneca: Current Employment. Stone: Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Janssen: Consultancy; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Boston Pharmaceuticals: Consultancy; GlaxoSmithKline: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Fathi: Foghorn: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Graubert: Janssen: Research Funding; astrazeneca: Research Funding; Calico: Research Funding.AZD6738 is being investigated in a number of malignancies including MDS and CMML

Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Komrokji: AbbVie: Consultancy; Acceleron: Consultancy; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Uy: AbbVie: Consultancy; Macrogenics: Research Funding; Agios: Consultancy; GlaxoSmithKline: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Astellas: Honoraria, Speakers Bureau; Jazz: Consultancy.CPX-351 (Vyxeos©; daunorubicin and cytarabine liposome for injection) is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes

Uy: Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; Agios: Consultancy; Jazz: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Macrogenics: Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Pusic: Syndax: Other: Advisory Board. Schroeder: Equillium Inc: Honoraria; Janssen: Honoraria; Sanofi Genzyme: Honoraria.

ABSTRACTInfection of mice with murine gammaherpesvirus 68 (?HV68; also referred to as MHV68) provides a tractable small-animal model with which to address the requirements for the establishment and maintenance of gammaherpesvirus infection in vivo. The M2 gene of ?HV68 is a latency-associated gene that encodes a protein lacking discernible homology to any known viral or cellular proteins. M2 gene transcripts have been detected in latently infected splenocytes (S. M. Husain, E. J. Usherwood, H. Dyson, C. Coleclough, M. A. Coppola, D. L. Woodland, M. A. Blackman, J. P. Stewart, and J. T. Sample, Proc. Natl. Acad. Sci. USA 96:7508-7513, 1999; H. W. Virgin IV, R. M. Presti, X. Y. Li, C. Liu, and S. H. Speck, J. Virol. 73:2321-2332, 1999) and peritoneal exudate cells (H. W. Virgin IV, R. M. Presti, X. Y. Li, C. Liu, and S. H. Speck, J. Virol. 73:2321-2332, 1999), as well as in a latently ?HV68-infected B-lymphoma cell line (S. M. Husain, E. J. Usherwood, H. Dyson, C. Coleclough, M. A. Coppola, D. L. Woodland, M. A. Blackman, J. P. Stewart, and J. T. Sample, Proc. Natl. Acad. Sci. USA 96:7508-7513, 1999). Here we describe the generation of ?HV68 mutants with disruptions in the M2 gene. Mutation of the M2 gene did not affect the ability of the virus to replicate in tissue culture, nor did it affect ?HV68 virulence in B6.Rag1 deficient mice. However, we found that M2 was differentially required for acute replication in vivo. While mutation of M2 did not affect acute phase of virus replication in the lungs of mice following intranasal inoculation, acute-phase virus replication in the spleen was decreased compared to that of the wild-type and marker rescue viruses following intraperitoneal inoculation. Upon intranasal inoculation, M2 mutant viruses exhibited a significant decrease in the establishment of latency in the spleen on day 16 postinfection, as measured by the frequency of viral genome-positive cells. In addition, M2 mutant viral genome-positive cells reactivated from latency inefficiently compared to wild-type and marker rescue viruses. By day 42 after intranasal inoculation, the frequencies of M2 mutant and wild-type viral genome-positive cells were nearly equivalent and little reactivation was detected from either population. In sharp contrast to the results obtained following intranasal inoculation, after intraperitoneal inoculation, no significant defect was observed in the establishment or reactivation from latency with the M2 mutant viruses. These results indicate that the requirements for the establishment of latency are affected by the route of infection.

ABSTRACTSeveral gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian D-type cyclins. In this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (?HV68) viral cyclin (v-cyclin). The ?HV68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a protein of approximately 25 kDa. To evaluate the effect of the ?HV68 v-cyclin on cell cycle progression in primary lymphocytes and to determine if the ?HV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lckproximal promoter to express the ?HV68 v-cyclin in early T cells. Expression of the ?HV68 v-cyclin significantly increased the number of thymocytes in cell culture, as determined by measuring both DNA content and incorporation of 5-bromo-2-deoxyuridine following in vivo pulse-labeling. Expression of the ?HV68 v-cyclin interfered with normal thymocyte maturation, as shown by increased numbers of CD4+CD8+double-positive thymocytes and decreased numbers of CD4+or CD8+single-positive and T-cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, ?HV68–v-cyclin–transgenic mice did not have proportionately increased thymocyte numbers, and staining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling demonstrated increased apoptosis in the thymi of v-cyclin-transgenic mice. Fifteen of 38 ?HV68–v-cyclin–transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the ?HV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the ?HV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the ?HV68 v-cyclin gene is an oncogene.

Jacoby: Jazz Pharmaceuticals:Research Funding;AbbVie:Research Funding.Finn:Jazz Pharmaceuticals:Speakers Bureau;Celgene:Speakers Bureau;Seattle Genetics:Speakers Bureau.Emadi:Jazz Pharmaceuticals:Research Funding;NewLink Genetics:Research Funding;Amgen:Membership on an entity's Board of Directors or advisory committees;KinaRx:Other: co-founder and scientific advisor;Genentech:Membership on an entity's Board of Directors or advisory committees;Servier:Membership on an entity's Board of Directors or advisory committees.Saba:Kyowa Kirin:Other: Advisory Board;Janssen:Other: Advisory Board, Speakers Bureau;AbbVie:Consultancy, Other: Advisory Board, Speakers Bureau;Pharmacyclics:Other: Advisory Board, Speakers Bureau;Kite:Other: Advisory Board.Powell:Pfizer:Research Funding;Novartis:Research Funding;Jazz Pharmaceuticals:Consultancy, Other: Advisor, Research Funding;Rafael Pharmaceuticals:Consultancy, Other: Advisor, Research Funding;Genentech:Research Funding.Seiter:Alexion:Speakers Bureau;AbbVie:Speakers Bureau;Onconova:Research Funding;Forma:Research Funding;Jazz Pharmaceuticals:Honoraria, Research Funding, Speakers Bureau;Sanofi:Honoraria, Speakers Bureau;Incyte:Honoraria, Speakers Bureau;Celgene:Honoraria, Research Funding, Speakers Bureau;Novartis:Honoraria, Research Funding, Speakers Bureau;Sun Pharma:Research Funding;Roche:Research Funding;Amphivena:Research Funding.Garcia:Jazz Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Faderl:Jazz Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.

Introduction: CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, has been approved by the US FDA and EMA for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes. The primary endpoint analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for the approvals evaluated older patients with newly diagnosed high-risk/secondary AML; after a median follow-up of 20.7 months, CPX-351 significantly improved median overall survival (OS) versus conventional 7+3 (9.56 vs 5.95 months; HR = 0.69 [95% CI: 0.52, 0.90]; 1-sidedP= 0.003), with a comparable safety profile and 2 infusion-related reaction events. After 5 years of follow-up, the improved median OS was maintained, with a HR (0.70) consistent with the primary endpoint analysis. Infusion-related reactions are generally common with liposomal drugs; this post-marketing observational study was therefore requested by the FDA to confirm observations from the phase 3 study by assessing the incidence and severity of infusion-related reactions during induction with CPX-351 in adults with AML.

Wei: Pfizer: Honoraria; Astellas: former employee, Honoraria; Novartis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax; Macrogenics: Honoraria; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Borate:Pfizer: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy. Fong:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy. Baer:Al Therapeutics: Research Funding; Kite: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Incyte: Research Funding. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Peterlin:AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Jurcic:Incyte: Consultancy; AbbVie Inc: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Forma Therapeutics: Research Funding; Kura Oncology: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Odenike:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Tanwani:AbbVie Inc: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees.Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in myelodysplastic syndromes, which is not an approved indication.

Cashen: Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. DiPersio:Incyte: Consultancy, Research Funding; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Amphivena Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy.

Jacoby: Celgene: Speakers Bureau; NovoNordisk: Consultancy. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: 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, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Multiple myeloma is the second most common hematologic malignancy in the US. The current standard of care for transplant eligible patients is therapy with high-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT). Although ASCT improves progression-free (PFS) and overall survival (OS), it is not curative and virtually all patients will relapse. Attempts to improve upon HDM by adding other agents to transplant protocols have largely resulted in unacceptable increases in toxicity.

Jacoby: NovoNordisk: Consultancy; Celgene: Speakers Bureau. Loken:Hematologics, Inc: Employment, Equity Ownership. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Vij:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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, Research Funding. Kahl:Gilead: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Acerta: Consultancy; Juno: Consultancy; Celgene: Consultancy.

The persistence of leukemic mutation(s) in AML patients who have achieved a morphologic complete remission (CR) after intensive induction chemotherapy is a strong predictor of early relapse and reduced overall survival (OS) (Klco JAMA, 2015; Morita, J Clin Oncol 2018; Jongen-Lavrencic, NEJM, 2018). There is no clinical consensus as to the optimal consolidation therapy for the ~50% of patients with intermediate-risk AML. The median relapse-free survival (RFS) for patients ≤60 years with ELN intermediate-risk disease is 0.8 years to 1.2 years, with a median OS of 1.2-2.1 years (Mrozek, J Clin Oncol, 2012). We have shown that intermediate-risk patients who clear all leukemia-associated mutations (LAMs) to a variant allele fraction (VAF) of <2.5% in first morphologic CR have a median event-free survival of 25.6 months, vs 8.8 months if they do not (HR 3.32). Median overall survival is 46.8 months if all LAMs are cleared, vs 19.3 months if they are not (HR 2.88). We hypothesized that improved post-remission risk stratification using LAM clearance can further refine risk assessment and optimize alloHCT decisions by identifying patients at lower risk of relapse, who might be expected to do well with standard chemotherapy.

Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Riedell: Novartis: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Speakers Bureau. Vij: Amgen: Honoraria, Research Funding; Jazz: Honoraria; Konypharma: Honoraria; Takeda: Honoraria, Research Funding; Bristol-Meyers-Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Abbvie: Honoraria.

MDS is an oligoclonal disease consisting of a founding clone and one or more subclones derived from the founding clone. Relapsed disease in myeloid malignancies is often characterized by the emergence of a subclone, presumably from selection pressure, following chemotherapy. The contribution of subclone evolution to MDS disease progression following an allogeneic hematopoietic cell transplant (alloHCT) has not been comprehensively studied.

Hypomethylating agents are standard first line therapy for older patients with AML and MDS. While these agents can prolong overall survival and disease free survival, they are not curative and only result in a complete response in about 20-25% of patients. For patients that fail these agents, there are no standard treatment options and overall survival is short at 4-6 months.

Selinexor is an oral, reversible, potent Selective Inhibitor of Nuclear Export / SINETMcompound that specifically blocks the protein Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1). Selinexor induces cell cycle arrest, inhibits DNA damage repair and modulates the expression of NF-κB in cancer cells lines and has demonstrated broad activity across several hematologic malignancies including AML. Our group has previously demonstrated that selinexor restores sensitivity to both cytarabine and anthracycline resistant AML cell lines. Furthermore, combination therapy with selinexor and cytarabine showed additive effects on inhibition of cell proliferation in vitroand prolonged the survival of leukemic mice in vivo. (Rettig et al., ASH 2013). For these reasons, we tested the safety and efficacy of selinexor in combination with chemotherapy in patients with relapsed or refractory AML.

Background: