Low-intensity chemotherapy, including HMAs or LDAC, in combination with VEN is a viable salvage option, even in multiply relapsed/refractory patients with AML, MDS, and BPDCN. Notable responses were identified in patients with diploid/intermediate cytogenetics, RUNX1, and/or IDH1/2 mutations.

Type I interferons (IFNs) are helical cytokines that have diverse biological activities despite the fact that they appear to interact with the same receptor system. To achieve a better understanding of the structural basis for the different activities of ␣ and ␤ IFNs, we have determined the crystal structure of glycosylated human IFN-␤ at 2.2-Å resolution by molecular replacement. The molecule adopts a fold similar to that of the previously determined structures of murine IFN-␤ and human IFN-␣ 2b but displays several distinct structural features. Like human IFN-␣ 2b , human IFN-␤ contains a zinc-binding site at the interface of the two molecules in the asymmetric unit, raising the question of functional relevance for IFN-␤ dimers. However, unlike the human IFN-␣ 2b dimer, in which homologous surfaces form the interface, human IFN-␤ dimerizes with contact surfaces from opposite sides of the molecule. The relevance of the structure to the effects of point mutations in IFN-␤ at specific exposed residues is discussed. A potential role of ligand-ligand interactions in the conformational assembly of IFN receptor components is discussed.

Background Malignancy-associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under-diagnosis or delayed diagnosis. Patients and Methods The University of Texas MD Anderson Cancer Center pathology database (1991–2014) was retrospectively interrogated for the keywords “hemophagocytosis” and/or “lymphohistiocytosis”. 77 adult patients were identified. All had an underlying malignancy. 16 patients with insufficient documentation were excluded. Results The majority of patients with pathologic evidence of hemophagocytosis/lymphohistiocytosis had incomplete work-up to confirm or refute HLH using the HLH-2004 criteria (HLH-2004 = 8 variables) and this is a common problem in adult HLH. Only 13/61 (21%) patients met the HLH-2004 diagnostic criteria based on available retrospective data. To identify potentially missed cases of HLH we reviewed published literature and selected additional variables known to be associated with adult HLH resulting in an extended diagnostic criteria of 18 variables. 35 patients met the extended criteria and 33 had follow-up data. The median OS of the 13 patients who met both the extended criteria and the HLH-2004 criteria was similar to the 20 patients who met the extended criteria but NOT the HLH-2004 criteria (1.43 vs 1.76 months, P=0.34) indicating similar underlying aggressive systemic process. 26 patients did not meet either criteria and 17 had follow-up data. The median OS of the 17 patients who had pathologic hemophagocytosis or lymphohistiocytosis but met neither criteria was significantly superior to those who met both the extended criteria and the HLH-2004 criteria or those who met the extended criteria but NOT the HLH-2004 criteria (17.27 vs 1.43 vs 1.76, P=0.002). Conclusion Addition of diagnostic laboratory variables that are more easily and rapidly available in smaller institutions and primary care settings than the HLH-2004 variables may be a good surrogate to raise early suspicion of malignancy-associated HLH. Prospective validation is warranted.

Myeloid neoplasms with germline DDX41 mutations have been incorporated into the 2017 WHO classification. Limited studies describing the clinicopathologic features and mutation profile are available. We searched for myeloid neoplasms with a DDX41 gene mutation tested by an 81-gene next-generation sequencing panel over a 7-month period. We identified 34 patients with myeloid neoplasms with DDX41 abnormalities; 26 (76%) men and 8 women (24%) [median age, 70 years], 20 acute myeloid leukemia (AML), 10 myelodysplastic syndrome (MDS), 1 chronic myelomonocytic leukemia (CMML) and 3 myeloproliferative neoplasms (MPN). Fiftynine DDX41 variants were detected: 27 (46%) appeared somatic and 32 (54%) were presumably germline mutations. The majority of presumed germline mutations were upstream of the Helicase 2 domain (93%) and involved loss of the start codon (30%).The majority of somatic mutations were within the Helicase 2 domain (78%), with the missense mutation p.R525H being most common (67%). There was a significant difference in the location of germline or somatic mutations (P < .0001). Concomitant mutations were detected involving 19 genes, but only TP53 (n = 11, 32%), ASXL1 (n = 8, 24%), and JAK2 (n = 4, 12%) were recurrent. Twenty (59%) patients showed diploid cytogenetics. Twenty-three (68%) patients presented with AML or MDS-EB-2, suggesting an association with high-grade myeloid neoplasm. Patients with myeloid neoplasms carrying DDX41 mutations show male predominance (3:1), higher age at presentation, association with TP53 mutations, and association with high-grade myeloid neoplasms in our cohort at a referral cancer center setting. These findings support the recognition of myeloid neoplasms with DDX41 mutation as unique, need for germline confirmation, and further assessment of family members.