- Blockade of GARP activation of TGF-β1 blocks murine primary myelofibrosis
- EVI1 promotes leukemogenesis through activation of ERG signaling
- Efficacy of JAK1 inhibition with itacitinib in low-risk acute GVHD
- A drug screen for agents that target endothelial cell–leukemia interactions to improve T-ALL therapy
- Unique characteristics of DDX41 mutation–associated myeloid neoplasms
- Review: bispecific antibodies for the treatment of B-cell lymphoma
Itacitinib monotherapy for GVHD, the role of ERG in EVI1-driven AML, and germline DDX41 mutations in myeloid neoplasms
In this week's episode, we’ll discuss the safety and efficacy of itacitinib monotherapy in low-risk acute GVHD, learn how ERG was discovered to be a key transcriptional target in EVI1-driven AML, and define a unique subtype of myeloid neoplasms characterized by germline DDX41 mutations.
EVI1-rearranged acute myeloid leukemia is an aggressive malignancy associated with chemotherapy resistance and poor prognosis. In this Plenary Paper, Schmoellerl and colleagues used both human and murine models and genome-wide CRISPR screens to characterize the downstream targets of EVI1. They identified ERG as a direct transcriptional target of EVI1 that blocks differentiation and facilitates self-renewal, suggesting a regulatory pathway potentially useful for targeted therapy.
Primary therapy for acute graft vs host disease (aGVHD) is systemic corticosteroids. Etra et al report on the results of a nonrandomized study of monotherapy with the selective JAK1 inhibitor itacitinib in 70 patients with low-risk aGVHD, compared to a contemporaneous cohort of steroid-treated patients. Responses to itacitinib were comparable to steroids (89% vs 86% at 28 days), with fewer serious viral and fungal infections with itacitinib, providing support for a randomized clinical trial in low-risk GVHD.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease that is supported by the tumor microenvironment. Cappelli and colleagues used primary T-ALL patient cells cocultured with endothelial cells (ECs) to delineate the role of ECs in chemoprotection of T-ALL cells and to screen for drugs to overcome that resistance. The authors identified 5 agents that improve survival in mouse xenografts, suggesting that the platform can be used to identify compounds that target tumor cell–EC interactions.
Detecting measurable residual disease beyond 10−4 by an IGHV leader-based NGS approach improves prognostic stratification in CLL
Two articles focus on the use of next generation sequencing (NGS) for the assessment of minimal residual disease (MRD). In the first article, Hengeveld et al report on a novel, academically developed immunoglobulin sequence-based NGS assay for quantitative detection of MRD in chronic lymphocytic leukemia (CLL). This technique, made available to other laboratories, has a range of detection that is more sensitive than conventional techniques and provides accurate prognostic stratification of patients with CLL. In the second article, Svaton et al compared allele-specific oligonucleotide polymerase chain reaction to NGS assay of immunoglobulin or T-cell receptor markers in pediatric B-cell acute lymphoblastic leukemia (ALL), again confirming that this is a reliable alternative for assessing MRD.
Makishima and colleagues report on a comprehensive characterization of 346 patients with myeloid neoplasms (MN) in the context of germ line DDX41 mutation and 525 first-degree relatives. Development of MN increased rapidly after age 40, with 49% developing MN by age 90. Computations were different from DDX41 wild-type patients, and when present, did not worsen the prognosis associated with this subset of MN.