Issue Archive

Patients with the heterogeneous disease follicular lymphoma who experience early progression (within 24 months of diagnosis [POD24]) have outcomes significantly inferior to those of the majority of patients, but prospective identification of POD24 is difficult. In this Plenary Paper, Claudel and colleagues use data from a prospective trial of modern therapies to evaluate the utility of combined end-of-induction measures with positron emission tomography/computed tomography and circulating tumor DNA as a composite biomarker for the prediction of POD24. They found very high specificity and sufficient sensitivity to recommend this combined imaging and genetic marker strategy in future trials that investigate preemptive interventions to circumvent early relapse.

This Perspective, from a doyen of allogeneic stem cell transplantation, focuses on what we do and do not know about the biology of both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) and how to apply this clinically. Socie highlights that we have gaps in knowledge for both but that they are larger for GVL. As well as providing views on ways forward for both, the article reflects on what we can learn from patients experiencing GVHD-free and relapse-free survival as the new immune system–host interplay in these patients delivers the clinical outcomes that we seek.

In a phase 1 trial, Davids et al evaluated brexucabtagene autoleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell product, in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). With responses largely restricted to patients with low levels of circulating disease, they demonstrate that efficacy of CD19 CAR T cells in CLL is tightly constrained by tumor burden. New strategies are needed to overcome the acquired T-cell dysfunction and suppressive microenvironment that characterize CLL and limit CAR T-cell expansion and persistence.

Aplastic anemia is an uncommon disease that is thought to be most commonly due to immune-mediated bone marrow (BM) destruction, but understanding of it has been limited by the inability to satisfactorily analyze the cellular landscape of near-empty BMs. Pool et al used imaging mass cytometry of BM samples from patients at diagnosis and 6 months after treatment with antithymocyte globulin (ATG) and identify specific multicellular lymphoid-dominant clusters developing within the BM at diagnosis, which accumulate activated macrophages. Over time, the normal cellular component is depleted, resulting in a hypocellular BM, with only few differentiated effector cells remaining; this evolution is reversed after responses to ATG. These findings extend our understanding of the pathogenesis of aplastic anemia and highlight how inflammation plays an important role.

Both CALRdel52 (type 1) and CALRins5 (type 2) mutant calreticulins bind the thrombopoietin receptor and activate JAK/STAT signaling driving myeloproliferative neoplasia, but biologically the mutations are not functionally identical. Arellano et al report that type 2 CALR mutations, but not type 1 mutations, stimulate activating transcription factor 6 (ATF6), leading to upregulation of the antiapoptotic protein BCLxL. Type 2 mutant cells are highly dependent on ATF6 and sensitive to BCLxL inhibition but insensitive to BCL2 inhibition. This work reveals a potential therapeutic vulnerability in type 2 CALR-mutant myeloproliferative neoplasms.

Some patients with hemophilia A develop antibodies that block factor VIII (FVIII) replacement therapy. Jing and colleagues used a murine model to discover that FVIII immunization induces follicular regulatory T (TFR) cell activation and expansion. TFR cells regulate FVIII-specific B-cell responses and immunoglobulin G subclass switching during FVIII inhibitor development, and imbalance between follicular helper T cells and TFRs is essential for FVIII inhibitor development. Understanding how immune cells contribute to inhibitor formation could enable prevention in the future.

The approved checkpoint inhibitors (CPIs) nivolumab and pembrolizumab show high response rates in recurrent or refractory Hodgkin lymphoma, but relapse is common and cure uncommon, while allogeneic stem cell transplantation (alloSCT) is curative in >50% of cases. To assess the effects of prior checkpoint inhibition, Perales and colleagues analyzed data from 2186 adult patients with relapsed Hodgkin lymphoma who underwent alloSCT, finding that, while rates of significant acute graft-versus-host disease (GVHD) were higher in these patients than in those who did not receive CPI therapy, progression-free survival was higher in patients with prior checkpoint inhibition because of less frequent relapses. The authors also identified use of posttransplant cyclophosphamide for GVHD prophylaxis as positively associated with improved outcomes in patients receiving CPIs.