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•Germ line ERG LOF variants predispose to cytopenias and HMs.•Somatic genetic rescue of ERG pathogenic variants in hematopoietic tissues impacts diagnosis, disease severity, and potential for correction.

Sickle cell disease (SCD) is characterized by increased hemolysis, which results in plasma heme overload and ultimately cardiovascular complications. Here, we hypothesized that increased heme in SCD causes upregulation of heme oxygenase 1 (Hmox1), which consequently drives cardiomyopathy through ferroptosis, an iron-dependent non-apoptotic form of cell death. First, we demonstrated that the Townes SCD mice had higher levels of hemopexin-free heme in the serum and increased cardiomyopathy, which was corrected by hemopexin supplementation. Cardiomyopathy in SCD mice was associated with upregulation of cardiac Hmox1, and inhibition or induction of Hmox1 improved or worsened cardiac damage, respectively. Because free iron, a product of heme degradation through Hmox1, has been implicated in toxicities including ferroptosis, we evaluated the downstream effects of elevated heme in SCD. Consistent with Hmox1 upregulation and iron overload, levels of lipid peroxidation and ferroptotic markers increased in SCD mice, which were corrected by hemopexin administration. Moreover, ferroptosis inhibitors decreased cardiomyopathy, whereas a ferroptosis inducer erastin exacerbated cardiac damage in SCD and induced cardiac ferroptosis in nonsickling mice. Finally, inhibition or induction of Hmox1 decreased or increased cardiac ferroptosis in SCD mice, respectively. Together, our results identify ferroptosis as a key mechanism of cardiomyopathy in SCD.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

Tremblay and colleagues asked whether patients receiving either routine anticoagulation or antiplatelet therapy for existing conditions prior to becoming ill with COVID-19 have different outcomes from patients receiving neither therapy. After matching for existing comorbidities, this retrospective observational study finds no evidence for an effect of prediagnosis anticoagulation on mortality.

There remain gaps in our knowledge of hereditary and sporadic causes of hematological malignancy (HM) and bone marrow failure (BMF) that prevent optimal diagnosis, disease surveillance and treatment. Here we report the discovery of ERGas a novel predisposition gene for BMF and HM. ERGis a known oncogene, typically via gene-fusions, leading to dysregulated ERG overexpression in blood and solid cancers. We identified a germline ERG ETS domain variant p.Y373C segregating with thrombocytopenia in a mother, who progressed to AML (27 yr) and then therapy-related MDS (35 yr), and in her 2 sons. All three showed copy neutral loss of heterozygosity of all or part of chromosome 21q, including the ERG locus, with the oldest son showing at least 2 somatic genetic rescue (SGR) events. The possibility of causal RUNX1variants were ruled out, with the smallest somatic cnLOH event beginning within the RUNX1gene, but not encompassing the RUNT domain where the majority of pathogenic missense variants are located. ERG, a highly constrained gene (LOEUF <0.33), is critical for definitive hematopoiesis, adult hematopoietic stem cell (HSC) function and platelet maintenance. An identical corresponding heterozygous germline variant (p.Y343C) in ERG’sclosest gene by homology, FLI1, causes platelet-type bleeding disorder-21 (BDPLT21, OMIM #617443).

While ex vivogene editing of CD34 +hematopoietic stem and progenitor cells (HSPCs) offers potentially curative therapies for patients with serious diseases, such as sickle cell anemia, significant autologous hematopoietic stem cell (HSC) transplant-related challenges remain, notably the requirement of myeloablative conditioning using chemotherapeutic agents such as busulfan. To address this challenge, we have developed a non-genotoxic conditioning strategy with our Engineered Stem Cell Antibody Paired Evasion (ESCAPE) approach where we aim to engineer the epitope of the HSC surface protein CD117 (cKIT) using base editors, in such a way that the engineered protein retains the normal CD117 receptor function, but escapesrecognition by a cognate monoclonal antibody that recognizes the wildtype CD117 protein. The ESCAPE-CD117 edit can be combined with a therapeutic target edit to generate a multiplex-edited engineered HSC (eHSC).

Introduction

Introduction

Introduction:Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival. The standard of care for HR-MDS are hypomethylating agents (HMA). The addition of venetoclax (Ven) to HMA has been shown to improve outcomes in acute myeloid leukemia (AML) and potentially in HR-MDS. The combination of oral decitabine/cedazurridine (DEC-C) with Ven has been shown to induce high response rates in patients with HR-MDS. Herein we analyze the responses of patients treated with DEC-C with Ven according to different response criteria. Additionally, we analyze the cytogenetic responses and mutation dynamics.

Introduction

Background

Introduction:Treatment of older patients (pts) with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). The optimal induction CT and consolidation regimens for older PCNSL pts is unknown. Moreover, there are few large scale prognostication studies available, including analysis of geriatric assessments (GA). We analyzed detailed characteristics, treatment patterns and outcomes with prognostication across 17 academic centers.

1)The first full-length structures of human arachidonate 12S-Lipoxygenase (12-LOX) reveal mechanisms of oligomeric and conformational states2)The structures uncover natural inhibitor of 12S-Lipoxygenase (12-lox) and reveal a binding site of inhibitor ML355

Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 independent cell-based chemical screens and identified the antimicrobial ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low-micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron, and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma.

Patent lymphatic filariasis is characterized by antigen-specific T-cell unresponsiveness with diminished IFN-γ and IL-2 production and defects in dendritic cell (DC) function. Because Toll-like receptors (TLRs) play an important role in pathogen recognition and TLR expression is diminished on B and T cells of filaria-infected individuals, we examined the effect of live microfilariae (mf) on expression and function of TLRs in human DCs. We show that mf-exposed monocyte-derived human DCs (mhDCs) demonstrate marked diminution of TLR3 and TLR4 mRNA expression compared with mf-unexposed mhDCs that translated into loss of function in response to appropriate TLR ligands. Exposure to mf significantly down-regulated production of IFN-α, MIP-1α, IL-12p70, and IL-1α following activation with poly I:C, and of IL-12p40 following activation with poly I:C or LPS. mRNA expression of MyD88, the adaptor molecule involved in TLR4 signaling, was significantly diminished in mhDCs after exposure to mf. Moreover, mf interfered with NF-κB activation (particularly p65 and p50) following stimulation with poly I:C or LPS. These data suggest that mf interfere with mhDC function by altering TLR expression and interfering with both MyD88-dependent signaling and a pathway that ultimately diminishes NF-κB activity. This down-regulated NF-κB activity impairs mhDC-produced cytokines needed for full T-cell activation.

Verstovsek: Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; CTI Biopharma Corp: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; Roche: Research Funding; ItalPharma: Research Funding. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Plexxikon: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Cellectis: Research Funding; MustangBio: Honoraria; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; Pacylex Pharmaceuticals: Consultancy; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support. Kantarjian:Immunogen: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Astex: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding.

No relevant conflicts of interest to declare.

Background

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic on March 11, 2020. This novel virus can cause a rapid progression from cough to acute respiratory distress syndrome and death. Cancer patients infected with COVID-19 were reported to have a 39% incidence of severe events, including admission to intensive care unit (ICU), mechanical ventilation, or death. Patients with hematologic malignancies, especially those undergoing treatment, are a particularly at-risk population due to disease-related impairment of the immune system and chemotherapy-induced neutropenia. The goal of this study is to analyze outcomes of COVID-19 infected patients with hematologic malignancies in order to better understand the impact of SARS-CoV-2 on this vulnerable population.

Mehta: Takeda: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Merck: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Affimed: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding. Trněný:AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Amgen: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Walewski:Servier: Consultancy, Honoraria; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Ribrag:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding. Dartigeas:Janssen: Honoraria; Roche: Honoraria; Gilead: Other: non-financial support. Pane:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Rodríguez:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zinzani:TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction:There are few data about prognostication and outcomes in patients (pts) with HIV-BL treated in the cART era. Optimal treatment strategies to minimize treatment-related mortality (TRM) remain unclear and current recommendations are based on small studies. We conducted a multicenter international analysis to identify prognostic factors and outcomes in pts with HIV-BL treated in the cART era.

Background

Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirty-two patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P = .002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P = .003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P = .016), a lower duration of pretherapy platelet transfusions (P = .013), and higher pretherapy platelets (P = .003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed sideroblasts; and 2 had RA with excess blasts. By ITT analysis, 19% of patients (16 of 83) responded, and when only evaluable patients were analyzed, 31% (16 of 51) responded. It was concluded that thalidomide, as a single agent, is effective in improving cytopenias of some MDS patients, especially those who present without excess blasts.

Thirty-five patients with myelodysplastic syndrome (MDS) were registered on protocol MDS 96-02 and were receiving continuous therapy with pentoxifylline 800 mg 3 times a day and ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M2, 300 mg/M2, and 400 mg/M2) to cohorts of 10 patients each. Therapy has been continued for 1 year in responders. Twenty-nine have completed at least 12 weeks of therapy and are available for response evaluation. Of the 21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five had secondary MDS. No differences were noted in response rates among the 3 dose levels. Seven patients did not respond at all, and 22 showed an improvement in cytopenias (76%). Three had a triple lineage response, 10 had a double lineage response, and 9 had a single lineage response (8 of 9 in absolute neutrophil count [ANC] and 1 had more than a 50% reduction in packed red blood cell transfusions). Fifteen patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved ANC, 11 of 22 demonstrated more than 50% reduction in blood transfusions, improved Hb levels, or both, and 7 of 22 showed improvement in platelet counts. Interestingly, the responses were frequently slow to appear, and continued improvement in counts was seen up to 12 months of therapy and beyond. This study supports the feasibility of treating patients with MDS with the unique approach of cytoprotection and anticytokine therapies as well as the principle that prolonged commitment to treatment is desirable when noncytotoxic agents are administered.

Introduction

Background

Background

Background: Hypomethylating agents (HMA) are the only approved agents to treat CMML. Phase III trials for HMA included few patients (pts) with myelodysplastic CMML (MD-CMML) but excluded pts with myeloproliferative CMML (MP-CMML). In pts eligible for Dacota trial (Itzykson et al Blood (2020) 136 (Supplement 1): 53-54), the reported outcomes have been variable in those treated with HMA. Therefore, we sought to define the outcomes of pts with CMML treated with HMA stratified by disease subtype.

Background:In patients with newly diagnosed (ND) NPM1-mutated acute myeloid leukemia (NPM1 mutAML), presence of measurable residual disease (MRD), as determined by quantitation of NPM1 muttranscripts is an independent prognostic marker (Ivey, NEJM, 2016). MRD assessed by multi-parameter flow cytometry (MFC-MRD) at the end of 2 induction cycles is considered highly prognostic in pts with standard risk NPM1wild typeAML (Freeman, JCO, 2018). The value of MFC-MRD is not well-established in patients with ND NPM1 mutAML.

Introduction:Mutated Nucleophosmin 1(NPM1 mut) is the most common genetic alteration in AML, seen in 30-35% of newly diagnosed cases. NPM1 mutis associated with a favorable prognosis in newly diagnosed AML. However, the prognostic impact of NPM1 mutin R/R AML has not been defined. We conducted an analysis to characterize the impact of NPM1muton outcomes of patients (pts) with R/R AML and the impact of specific therapies in R/R NPM1 mutAML.

Introduction

Background:Mantle cell lymphoma (MCL) is an aggressive type of non‐Hodgkin lymphoma (NHL) and accounts for 6% of all NHL cases in Western countries (Thandra KC. Med Sci.2021;9:5). First-line treatment options are not curative and most patients (pts) experience relapse (Wu H. Front Oncol.2020:10:588314; Kumar A. Blood Cancer J. 2019;9:50). Targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors, are used as second- and later-lines; however, treatment intolerance and failure are common with poor survival outcomes (Epperla N. Hematol Oncol.2017;35:528-35; Jain P. Br J Haematol.2018;182:404-11). Thus, novel therapies are needed for pts with relapsed or refractory (R/R) MCL. Parsaclisib is a potent, highly selective, next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) δ. Here, we report results of the primary analysis of the cohort of BTK inhibitor-naive pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544, EudraCT 2017-003148-19).

Background:The oral Bcl-2 inhibitor venetoclax (Ven) has preclinical activity in acute lymphoblastic leukemia (ALL) and has shown encouraging response rates in combination with the Bcl-xL inhibitor navitoclax in patients (pts) with relapsed/refractory (R/R) ALL. We hypothesized that the addition of Ven to low-intensity chemotherapy with mini-hyper-CVD may improve outcomes in pts with ALL.

Background: Treated secondary acute myeloid leukemia (ts-AML), defined as AML arising from previously treated antecedent hematologic disorder, is a high-risk disease with dismal outcomes. CPX-351 is approved for the treatment of secondary AML, although it did not improve outcomes within the subgroup of patients (pts) with secondary AML with prior exposure to hypomethylating agents (HMAs). In clinical practice, either chemotherapy or HMA plus venetoclax (Ven) are often used for pts with ts-AML, although there are little data to guide the optimal therapy in this setting