Issue Archive

Saliba and colleagues use 4 illustrative cases to delineate diagnosis and treatment of non-transfusion-dependent β-thalassemia. The authors discuss their approach to diagnosis, the use of transfusion and novel agents including luspatercept, and the use of chelation therapy in iron overload. Throughout, they emphasize the management of organ-specific morbidity in this complex, multisystem disease.

Huber et al report on the final results of a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in 41 patients with previously untreated high-risk chronic lymphocytic leukemia (CLL) with del(17p) or TP53 mutation. Results in these high-risk patients were encouraging, with a 3-year progression-free survival of 79.9% and overall survival of 92.6%. This combination is a promising first-line treatment for patients with high-risk CLL.

Up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) relapse with chemoresistant disease. Zhou and colleagues report that inactivation of the E3 ubiquitin ligase KLHL6 promotes chemoresistance in DLBCL by preventing proteasomal degradation of NOTCH2. In addition, mutations in NOTCH2 can also prevent proteasomal degradation. NOTCH2 upregulates RAS signaling, and in vitro studies in chemoresistant cells suggest that cells with either KLHL6 inactivation or NOTCH mutation respond to nirogacestat, a γ-secretase inhibitor that blocks NOTCH signaling, in combination with the AKT inhibitor ipatasertib, which downregulates RAS signaling.

Abnormal innate immune signaling in myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) suggests a novel pathway for targeted therapy. The kinase IRAK4 has been implicated in immune dysregulation in MDS/AML but, despite encouraging early clinical trials, therapy with an IRAK 4 inhibitor appears insufficient as monotherapy. Bennett et al report that IRAK4 inhibition induces compensatory IRAK1 upregulation, limiting therapeutic efficacy; however, simultaneous targeting of both IRAK1 and IRAK4 results in greater suppression of leukemic stem cells in in vitro studies and in mouse xenografts.

Chronic graft-versus-host disease (cGVHD) has many features resembling autoimmune diseases such as scleroderma. Alloantibodies against H-Y antigens, encoded on the Y chromosome, are a risk factor for cGVHD in female-into-male transplantation. Umino and colleagues investigated the link between these 2 observations and demonstrate that, although H-Y proteins are usually expressed only intracellularly, specific HLA class II alleles transport H-Y antigens to the endothelial cell surface and induce antibody production; these antibodies contribute to both cGVHD and the graft-versus-leukemia (GVL) effect.