Warm autoimmune hemolytic anemia (wAIHA) is a rare, life-threatening disease characterized by autoantibody-mediated destruction of red blood cells with no approved treatments. Nipocalimab, an immunoselective neonatal Fc receptor blocker, reduces circulating IgG levels, including autoantibodies implicated in wAIHA. The phase 2/3, randomized, 24-week, double-blind ENERGY study in participants with wAIHA evaluated nipocalimab 30 mg/kg IV q4w (n=38), 15 mg/kg IV q2w (n=38), and placebo (n=39). The primary endpoint, durable hemoglobin response (hemoglobin ≥10 g/dL and a ≥2 g/dL increase from baseline at 3 consecutive visits [≥28 days] starting by Week 16, without rescue therapy), achieved statistical significance for nipocalimab 30 mg/kg IV q4w (23.7% [9/38]; 1-sided P=0.015) but not 15 mg/kg IV q2w (21.1% [8/38]; P=0.044; not significant) versus placebo (7.7% [3/39]). Improvement in FACIT-Fatigue score at Week 24 (key secondary endpoint) was observed with nipocalimab, with mean (SD) improvement of 3.4 (7.29) points (nominal P=0.007) for 30 mg/kg IV q4w and 1.2 (6.07) (nominal P=0.267) for 15 mg/kg IV q2w versus 0.6 (3.42) for placebo. Mean percent (SD) reduction in average daily prednisone dose (key secondary endpoint) was 15.1% (28.2) for nipocalimab 30 mg/kg IV q4w (nominal P=0.039) and 14.0% (30.4) for 15 mg/kg IV q2w (nominal P=0.055) versus 3.9% (16.33) for placebo. The safety profile was consistent with the known safety profile of nipocalimab and with wAIHA-associated risks. Overall, in the double-blind ENERGY study, nipocalimab demonstrated rapid hemoglobin response and nominal improvements in fatigue that were maintained over 24 weeks, with no new safety findings in wAIHA. NCT04119050.

Chromosomal translocations involving nucleoporin (NUP) loci, such as NUP98 and NUP214, are recurrent in acute myeloid leukemia (AML). However, the intrinsic functions of wild-type nucleoporins in AML remain largely unknown. By screening the NUP family, we identified NUP214 as a frequently overexpressed gene and a critical fitness determinant in leukemia stem cells (LSCs). NUP214 acts as a conserved driver of LSC survival by restricting heme catabolism, limiting Fe[2+] accumulation, and suppressing lipid peroxidation. Conversely, NUP214 deficiency leads to upregulation of heme oxygenase 1 (HMOX1) and arachidonate 15-lipoxygenase (ALOX15), causing heme exhaustion and excessive lipid peroxidation, which ultimately triggers ferroptosis in LSCs and impairs AML progression. Mechanistically, NUP214 translocates into the nucleoplasm where it blocks Sub1-mediated RNA polymerase II recruitment to repress transcription of the key pro-ferroptotic genes HMOX1 and ALOX15, revealing a non-canonical role beyond its nuclear pore function. Furthermore, we developed the small-molecule compound 0449-b, which acts as a selective NUP214 degrader by recruiting NUP214 to the Cullin5-Rbx2 E3 ligase complex, inducing its neddylation and proteasomal degradation. 0449-b potently triggers LSC ferroptosis and exhibits anti-leukemic activity in vivo, while sparing normal hematopoietic stem cells. Collectively, our findings establish NUP214 as a critical oncoprotein that orchestrates heme metabolism and lipid peroxidation to sustain LSCs, and highlight NUP214-targeted degradation as a promising intervention strategy for AML.

Large granular lymphocytic leukemia (LGLL) is an uncommon and likely under-diagnosed leukemia that causes severe neutropenia and anemia and can have profound effects on the quality of life for afflicted patients. Frequently associated with various auto-immune phenomena, LGLL is a paradigm for a highly interdisciplinary disease. Recent advances in our pathobiological understanding of LGLL, along with the development of novel agents, have stimulated a growing number of clinical trials and innovative approaches targeting this disease. Currently, the absence of uniform diagnostic and response criteria for LGLL results in significant heterogeneity in diagnosis and response assessment across studies. Furthermore, with the emergence of a variety of novel experimental therapeutics and an increasing number of clinical trials, it becomes critical to better define the key diagnostic, treatment and response parameters for this disease. The International LGLL Consortium was created to develop cross-disciplinary expert consensus on uniform diagnostic, treatment, and response criteria for LGLL suitable for both routine clinical use and interventional trials while facilitating cross-study comparisons. Utilizing an evidence-based framework, along with the international panel that comprises the LGLL Consortium, this report delineates the key criteria that will serve as a foundation for both the clinical management and future investigations in LGLL.

Gene mutations and chromosome abnormalities are important components of prognostication in acute myeloid leukemia (AML). Here we assessed whether DNA methylation patterns in AML patients can augment risk assessments provided by genetic and other markers to better predict outcomes. Unsupervised DNA methylation patterns separating patients into 13 DNA methylation subtypes (epitypes) were used to classify 1,262 patients with de novo AML. Epitypes were predominantly comprised of a predominant genetic alteration; however, some patients within epitypes lacked cardinal alterations and were termed genetic alteration-like. Interestingly, patients displaying alteration-like DNA methylation patterns of CEBPAbZIP, FLT3-ITD, core-binding factor, KMT2A-rearrangements and other abnormalities displayed outcomes similar to patients with actual cardinal alterations. We further derived a DNA methylation signature enriched in patients with FLT3-ITD mutations that involved hypomethylation of STAT binding sites, termed the STAT hypomethylation signature (SHS). SHS positivity identified patients with inferior outcomes further adding to the prognostic significance of FLT3-ITD. Machine learning modeling revealed these DNA methylation signatures together significantly added to genetic, demographic and clinical markers to predict remission, relapse and overall survival. In summary, DNA methylation signatures capture patients who mimic cardinal genetic mutations providing additional prognostic information that may be used to in concert with standard genetic markers.

Despite advances in the molecular characterization of mature T and NK cell lymphomas, outcomes for these patients is poor especially those with relapsed/refractory (R/R) disease. These tumors possess mutations that often result in tonic T cell receptor (TCR) signaling and an immunosuppressive tumor microenvironment. Interleukin-2-inducible T cell kinase (ITK) plays an important role in TCR signaling and T cell differentiation. Soquelitinib is a covalent oral selective ITK inhibitor that blocks Th2 differentiation while sparing Th1 cells (Th1 skewing). We conducted a phase 1 trial with soquelitinib for the treatment of R/R peripheral T cell lymphomas to determine safety, target occupancy and antitumor activity. A dose escalation design was followed by an expansion cohort to confirm dosing and identify predictive characteristics. Seventy-five patients were enrolled. No dose-limiting toxicities were observed with doses up to 600mg BID and target occupancy exceeding 80% was established for 200mg BID dose. At the 200mg BID dose, number of prior lines of therapy was found to affect antitumor activity as durable complete and partial responses were seen in 37% patients with 1-3 prior therapies; no responses were seen in patients with >3. Objective and durable tumor responses were observed in various histologic subtypes. Blood and tumor biopsies indicated that soquelitinib treatment leads to Th1 skewing, reduction of T cell exhaustion and blockade of Th2 cells. These studies demonstrate soquelitinib is active in T cell lymphomas with a mechanism related to effects on malignant T cells and/or normal T effector cells. Trial registration: NCT03952078 at www.ClinicalTrials.gov.