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The severity and mortality of COVID-19 and seasonal influenza were recently compared in the general population but not in patients with hematological malignancies. We analyzed the clinical courses of 79 patients with hematological malignancies and diagnosis of either SARS-CoV-2 (n = 29) or influenza A or B infections (n = 50) who were admitted or were already under treatment in the Department of Oncology, Hematology and Stem cell Transplantation at the University Medical Center Hamburg-Eppendorf, Germany, between 1 January 2012 and 31 January 2021. For COVID-19, we observed significantly higher rates of acute respiratory distress syndrome with 48% (14/29) compared to 14% (7/50) in the influenza group (p = 0.001) as well as a significantly higher virus-associated 90-day mortality (41% vs. 12%, p = 0.005). Based on our results, we conclude that infections with SARS-CoV-2 are more severe than influenza A or B in patients with hematological malignancies.

The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemia (AL) refer to hematological patients in general and are not focused on acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). We herein report a review of the current literature on adult AL patients infected with SARS-CoV-2. Overall, SARS-CoV-2-associated mortality ranges from 20–52% in patients with adult AL. AML patients have a particularly high COVID-19-related mortality. Of note, most of the available data relate to the pre-vaccination era and to variants before Omicron. The impact of COVID-19 infections on AL treatment is rarely reported. Based on the few studies available, treatment delay does not appear to be associated with an increased risk of relapse, whereas therapy discontinuation was associated with worse outcomes in AML patients. Therefore, the current recommendations suggest delaying systemic AL treatment in SARS-CoV-2-positive patients until SARS-CoV-2 negativity, if immediate AL treatment is not required. It is recommended to offer vaccination to all AL patients; the reported antibody responses are around 80–96%. Seronegative patients should additionally receive prophylactic administration of anti-SARS-CoV-2 monoclonal antibodies. Patients with AL infected with SARS-CoV-2 should be treated early with antiviral therapy to prevent disease progression and enable the rapid elimination of the virus.

Severe infectious complications remain the main cause of mortality in leukemia patients due to a long period of profound neutropenia. Standardized regimens for antimicrobial, antifungal, and antiviral prophylaxis and therapy in neutropenic patients have improved infection-associated mortality. Nevertheless, many patients are refractory to these multidrug approaches. Tigecycline is a last-resort antibiotic with a broad-spectrum activity; unfortunately, clinical experience in multidrug-resistant febrile neutropenia is limited. The aim was to evaluate the efficacy of tigecycline treatment in comparison to standard treatment in this patient cohort. In this single center analysis, we analyzed the clinical courses of 73 patients with acute leukemia and diagnosis of febrile neutropenia resistant to hospital-based multidrug escalation levels who continued on a standard approach without antibiotics as the last resort (n = 30) or were switched to tigecycline in addition to carbapenem treatment (n = 43). We observed comparable overall response rates (decrease in C-reactive protein or resolution of fever) in both patient cohorts. Switching the antibiotic approach to tigecycline showed lower absolute sepsis (33% vs. 47%, p = 0.235) and infection-associated mortality rates (5% vs. 13%, p = 0.221). Prospective larger randomized studies are necessary to underline these results and to be able to generate reliable statistics.

The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.

Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.

Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukemia (AL) patients still have considerable febrile neutropenia-related mortality. However, the diagnostic yield of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) in acute leukemia patients is unclear. In this retrospective single-center study, we analyzed 88 BAL samples of patients with acute leukemia and pulmonary infiltrates in spite of treatment with broad-spectrum anti-infective agents. The aim was to investigate the impact of FB with BAL on detecting causative organisms, which would result in a change in treatment regimens. The median age was 59 years, and 86% had acute myeloid leukemia. In 47%, pathogens were detectable in BAL fluid (pathogen bacteria, viruses, and fungi in 2, 15, and 18%, respectively), with Aspergillus fumigatus detected most frequently. BAL-guided anti-infective therapy changes were performed in 15%. The detection of herpes simplex and influenza viruses were the main reasons for treatment changes. Despite broad-spectrum anti-infective treatment, in approximately half of all patients, pathogens could still be isolated in BAL samples. However, consecutive changes in anti-infective treatment were considerably less frequent, with most changes performed in patients with Herpes simplex virus and Influenza A detection. The need for FB with BAL in patients with AL receiving broad-spectrum empiric anti-infective treatment should therefore be weighed carefully.

Multiple recent publications have described a highly aggressive subgroup of pediatric glioblastoma, which is clearly separable from other pediatric and adult glioblastoma based on its DNA methylation profile (GBM MYCN). These tumors almost exclusively occur in children and have a median overall survival of only 14 months. Many tumors in this group are driven by MYCN amplifications and harbor TP53 mutations. Otherwise, information about these tumors are still sparse and treatment is ineffective and causes severe side effects in many cases. In order to further investigate the biology and treatment options of these tumors, preclinical models are urgently needed. Here, we describe the generation of hGFAP-cre::TP53Fl/Fl::lsl-MYCN mice, which carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. These animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors by histology, global gene expression, and DNA methylation. In order to understand the developmental biology and intratumoral heterogeneity, we employed single cell RNA sequencing (scRNAseq) to the murine tumors with first results indicating a resemblance of tumor cells to committed oligodendrocyte precursors. We further show that both murine and human tumor cells are sensitive to AURKA inhibition in vitro, suggesting a potential new therapeutic option for improved patient care. We believe that further characterization and utilization of the model will pave the way to improved treatment strategies for patients with these highly aggressive tumors.

Key Points Patients with acute leukemia present with a prolonged and severe course of COVID-19, which is paralleled by high rates of viremia. Low-intensive chemotherapy seems to be more feasible in patients with acute myeloid leukemia and concomitant SARS-CoV-2 infection., Visual Abstract

Introduction Selinexor is an exportin-1 (XPO1) inhibitor which forces the nuclear retention and functional activation of tumor suppressor proteins, inducing apoptosis in cancer cells. Overexpression of XPO-1 is common in many tumors, including acute myeloid leukemia (AML). A phase II study, "SAIL", of selinexor with cytarabine and idarubicin in patients with relapsed/refractory AML was conducted by Fiedler et al. showing a high remission rate. To identify molecular predictors of response and survival we evaluated the molecular mutations and their course in selinexor treated patients. Methods All 42 patients treated in the SAIL trial were eligible to participate in this translational study. The main criterion for inclusion in the present study was availability of DNA from bone marrow or peripheral blood at 3 time points: initial AML diagnosis, screening for the SAIL trial and first response assessment on day 28 of cycle 1. A custom TruSight myeloid sequencing panel was used to identify molecular mutations at diagnosis. Molecular response was defined as variant-allele frequency (VAF) Results Eighteen patients were included for whom DNA was available for all three time points. The median age was 47.5 years (29-72), median prior therapies was 3 (1-9). 13 patients had de novo and 5 secondary/therapy-related AML. ELN risk at first diagnosis was favorable in eight, intermediate in five and adverse in three patients. Only one course of SAIL treatment was administered to all patients. 8 patients achieved morphologic complete remission (CR) or CR with incomplete hematologic recovery (CRi). 13 patients proceeded to allogeneic hematopoietic cell transplantation (alloHCT) or donor lymphocyte infusion. The median overall survival was 0.69 years. The molecular profile showed a predominance of secondary AML-type mutations. No clear pattern was found between mutation status and morphologic CR or CRi (Figure 1). Molecular response to the SAIL induction treatment was found in 6 of 14 patients who had a molecular marker. Mutations in FLT3 (FLT3-TKD=1, FLT3-ITD=2), SF3B1 and TP53 were associated with molecular response, whereas mutations in GATA2, CUX1, TET2, BCOR, DNMT3A, RAD21, ASXL1, SRSF2, and WT1 were associated with resistance. When comparing the molecular characteristics of patients achieving CR/CRi (n=8) and all other patients (n=10), a trend to achieve CR was observed among patients with NPM1 mutations (P=0.094), whereas mutations in ASXL1 (P=0.09) and SRSF2 (P=0.09) were associated with refractoriness. One of the responding patients received selinexor as maintenance therapy for four years. The patient was diagnosed with de novo AML with normal cytogenetics, with SF3B1 and SRSF2 mutations. The patient received an HLA-identical transplant after myeloablative conditioning, but relapsed 6 years after alloHCT. One cycle of selinexor/chemotherapy was administered and the patient achieved CR. The patient continued selinexor maintenance treatment with 60 mg selinexor twice a week. SF3B1 and SRSF2 mutations were still present at the time of relapse and declined under SAIL treatment (Figure 2). The patient received one course of DLI (1x10 7CD3 +), which was tolerated well without signs of GvHD. MRD remained detectable 17 days after DLI. At 30 days after DLI treatment both MRD markers were negative. Under continued selinexor maintenance treatment MRD remained negative until last follow-up at 4.9 years after SAIL treatment. The patient tolerated selinexor well with short-term nausea and dysgeusia after selinexor intake. Selinexor maintenance treatment was stopped 4 years after SAIL treatment and the patient remains in CR 14 months after the end of maintenance. Conclusion In this small series, we found a correlation between FLT3, TP53 and SF3B1 mutation status and molecular response to selinexor/chemotherapy (SAIL). NPM1 mutations were associated with morphologic response to SAIL by trend. Finally, selinexor maintenance may have contributed to long-term disease control in a patient with relapsed AML, and long term therapy with selinexor is feasible. Figure 1 Figure 1. Disclosures Fiedler: Servier: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; MorphoSys: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Celgene: Consultancy, Honoraria; Ariad/Incyte: Honoraria; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Modemann: Servier: Honoraria, Other: Travel accomodation; Incyte: Other: Travel accomodation; Gilead: Other: Travel accomodation; Jazz Pharmaceuticals: Other: Travel accomodation; Novartis: Other: Travel accomodation; Teva: Other: Travel accomodation; Pfizer: Other: Travel accomodation; Amgen: Other: Travel accomodation; Daiichi Sankyo: Research Funding; Abbvie: Honoraria, Other: Travel accomodation. Bokemeyer: Merck KGaA: Honoraria; Sanofi: Consultancy, Honoraria, Other: Travel accomodation; Roche: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; BMS: Honoraria, Other: Travel accomodation, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Lilly/ImClone: Consultancy; Merck Serono: Consultancy, Other: Travel accomodation ; Bayer Schering Pharma: Consultancy; GSO: Consultancy; AOK Health insurance: Consultancy; Abbvie: Research Funding; ADC Therapeutics: Research Funding; Agile Therapeutics: Research Funding; Alexion Pharmaceuticals: Research Funding; Amgen: Research Funding; Apellis Pharmaceuticals: Research Funding; Astellas: Research Funding; BerGenBio: Research Funding; Blueprint Medicine: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Gilead Sciences: Research Funding; Gylcotope GmbH: Research Funding; GlaxoSmithKline: Research Funding; Inside: Research Funding; IO Biotech: Research Funding; Isofol Medical: Research Funding; Janssen-Cilag: Research Funding; Karyopharm Therapeutics: Research Funding; Lilly: Research Funding; Millenium: Research Funding; MSD: Research Funding; Nektar: Research Funding; Rafael Pharmaceuticals: Research Funding; Springworks Therapeutics: Research Funding; Taiho Pharmaceutical: Research Funding; Pfizer: Other. Ganser: Celgene: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Thol: Astellas: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS/Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Heuser: Karyopharm: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Selinexor in patients with relapsed or refractory AML

Acute graft-versus-host disease (aGVHD) is a serious complication after stem cell transplantation and is associated with high non-relapse mortality. If steroid treatment as first-line therapeutic approach fails, treatment options are limited. In retrospective studies, ruxolitinib, a selective Janus kinase 1/2 inhibitor as well as extracorporeal photopheresis (ECP) could show high efficacy in treatment of steroid refractory acute and chronic GVHD. Here, we report single-center experience of combining JAK-inhibitor treatment with ECP in 18 patients with severe steroid refractory aGVHD of lower GI-tract. The treatment was well tolerated and no severe cytopenia (grade IV) occurred, in three patients grade III cytopenia could be observed. Response was complete or partial in 44% and 11%, respectively, resulting in an estimated 2 year overall survival of 56%. Steroids were tapered rapidly with a median time of 2 days for halving of dosage avoiding additional steroid-associated side effects. Under treatment with ruxolitinib and ECP, an increased level of regulatory T cells could be observed elucidating direct effects of this treatment on immune response.

Aberrant activation of hedgehog signaling (HH) is associated with a wide variety of neoplasms, including acute myeloid leukemia (AML). The GLI transcription factors are the main downstream effectors of the HH signaling cascade and play a fundamental role in cancer development, progression and maintenance of leukemic stem cells, which are responsible for therapy failure and tumor relapse due to their resistance to chemotherapy. Moreover, the GLI transcription factors represent central hubs in oncogenic signaling and thus are an attractive therapeutic target for anti-cancer therapy. However non-canonical GLI activation by multiple oncogenic signaling pathways limit the use of SMO inhibitors, while treatment strategies directly targeting the GLI transcription factors are limited. Mebendazole (MBZ) is a commonly used anthelmintic drug with a favorable toxicity profile. MBZ has been shown to exhibit strong anti-tumor effects in different cancer entities, including AML. We treated AML cell lines and primary AML samples with different MBZ concentrations and could show a dose-dependent effect on the proliferation, colony formation and apoptosis in AML cells. In addition, therapeutic synergy between cytarabine and MBZ was demonstrated in OCI-AML3 cells with a combination index To further evaluate if MBZ is a suitable GLI inhibitor in clinical practice, we transferred these findings into the clinical setting by treating two patients with refractory AML with MBZ monotherapy in an off-label setting. We demonstrated an effective MBZ concentration in the plasma using a modified plasma inhibitory assay (PIA) by incubating an indicator cell lines carrying the GLI luciferase promoter transgene with the patient's plasma. In one patient, a clear continuous decrease in leukemic blasts in peripheral blood was noted. In this patient a reduction in the luciferase activity in the PIA assay and a fast reduction in GLI2 levels in peripheral leukemic blood were detected. Moreover, a healthy volunteer ingested MBZ at a dose of 50 mg/kg divided in two doses at time 0h and 12h. Blood was drawn at 4h and at 24h. PIA results indicated a biological active plasma concentration. Taken together, our results demonstrate that MBZ functions as an effective GLI inhibitor with strong anti-leukemic activity in a clinical setting and encourage for further studies to translate the scientific findings into clinical practice. A clinical study of mebendazole plus low dose cytarabine in patients with refractory AML is planned. Figure Disclosures Stamm: AstraZeneca: Employment. Modemann:Servier, Incyte, Gilead, Jazz Pharmaceuticals, Novartis, Teva, Pfizer, Amgen: Other: Support for meeting attendance ; Servier: Honoraria; Daiichi Sankyo: Research Funding. Fiedler:Amgen, Pfizer, Abbvie: Other: Support in medical writing; Amgen: Research Funding; Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, Jazz Pharmaceuticals, Daiichi Sanchyo Oncology, Servier: Other: Support for meeting attendance. OffLabel Disclosure: Mebendazole is an approved oral broad-spectrum anthelmintic drug for the treatment of worm infections. Data from preclinical studies demonstrated strong anti-tumor effects. We used it as an antineoplastic drug in a compassionate and off-label setting for treatment of two AML patients.