Issue Archive

Aoki and Steidl review the impact of single-cell technologies on the understanding of the heterogeneity of malignant cells and their microenvironment. Using classic Hodgkin lymphoma as a paradigm, the pair describe how single-cell sequencing and multiplexed imaging allows elucidation of the biology of a disease where a small number of tumor cells are embedded in a complex collection of nonmalignant cells in the tumor microenvironment.

Gossai et al report on the prognostic implications of central nervous system (CNS) involvement in newly diagnosed T-cell acute lymphoblastic leukemia. Pooling data from 2 large trials with different regimens and divergent uses of CNS prophylaxis, the authors analyzed the impact of CNS-1 (no blasts), CNS-2 (0-5% blasts), and CNS-3 (>5% blasts) on outcomes. CNS-1 and CNS-2 have similar event-free survival (EFS) and overall survival (OS), whereas CNS-3 has inferior EFS and OS. Nelarabine improves survival in patients with CNS-3 in a regimen including CNS radioprophylaxis.

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by somatic mutation of the PIGA gene, leading to a loss of erythrocyte complement inhibitory proteins and complement-mediated hemolysis. Prata and colleagues report on the surprising finding that patients with PNH also have a markedly increased prevalence of associated germline mutations in complement factor H (CFH), affecting both their clinical course and response to eculizumab. Patients with CFH variants had higher rates of transfusion, thrombosis, and poor response to eculizumab.

Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.

Therapy-related acute myeloid leukemia (t-AML) is viewed as carrying a poor prognosis; however, Othman et al demonstrate that prognosis for t-AML is actually quite heterogeneous, with isolated NPM1 mutation portending a good prognosis in both de novo AML and t-AML. NPM-mutated t-AML nearly always has a normal karyotype and is associated with DNMT3A and TET2 mutations, similar to the signature of de novo NPM-mutated AML. These data suggest that, unlike most t-AML, NPM-mutated t-AML should be viewed as comparable to de novo disease and should not be considered for early stem cell transplant.

Sparkenbaugh and colleagues investigated the role of factor XII (FXII) in sickle cell disease (SCD)-related thrombo-inflammation. Patients with SCD have increased markers of activation of FXII and the contact pathway of coagulation. In the Townes mouse model of SCD, FXII contributes to thrombin generation and inflammation after challenge with TNFα, and FXII inhibition reduces venous thrombosis, congestion, and microvascular stasis. FXII inhibition may offer a novel approach to reducing thrombo-inflammation in SCD without incurring increased bleeding risk.

Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.