Issue Archive

Chelation therapy in patients with low-risk myelodysplastic syndrome (MDS) and iron overload reduces iron burden, but whether it changes the natural history of the disease or improves survival is unknown. Antypiuk and colleagues stringently tested the consequences of progressive iron overload in a murine model of MDS, demonstrating exacerbation of marrow failure, inferior leukemia-free survival, and inferior overall survival. With early iron restriction using a ferroportin inhibitor, erythropoiesis and survival outcomes improved and were enhanced further when luspatercept was added, providing highly persuasive mechanistic evidence for earlier intervention to limit iron in patients with MDS.

With the development of chimeric antigen receptor T-cell therapy and biologicals that engage both malignant B cells and normal T cells, the scene is set to establish whether advanced stage follicular lymphoma can be cured through stimulation of an effective immune response. In this Blood Spotlight, Iacoboni and Morschhauser succinctly review current T-cell–redirecting strategies in follicular lymphoma, synthesizing the data and providing practical advice on sequencing for treating physicians and looking ahead to what may be achievable in the next decade.

Since the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), major advances in first-line therapy of large B-cell lymphomas have proved elusive, but encouragingly, multiple new agents with different mechanisms of action and sensitive markers of response are entering the fray. Qualls et al review the landscape of current trials that are due to read out in the next few years, highlighting the strategies being tested and anticipated issues around interpretation in an evolving clinical space.

Risk classification for pediatric B-cell acute lymphoblastic leukemia (B-ALL) enables intensity and duration of therapy to be tailored, and the process for defining low- and high-risk is iterative as regimens are tested in prospective trials. Purvis and colleagues report on outcomes for children with favorable prognosis ETV6::RUNX1 or high-hyperdiploid B-ALL in St. Jude studies. The authors report that patients with ETV6::RUNX1 B-ALL are ideal candidates for therapy de-escalation and that assessment of minimal residual disease identifies patients with high-hyperdiploid B-ALL who require intensified therapy, thereby further refining risk-classification algorithms.

The G protein–coupled receptor class C group 5 member D (GPRC5D) is highly expressed by malignant plasma cells, making it an attractive therapeutic target, with 1 GPRC5D-targeted T-cell–engaging bispecific antibody already approved. In preclinical models, Eckmann and colleagues evaluated forimtamig, a novel bispecific antibody featuring a 2:1 asymmetrical configuration with bivalent GPRC5D binding sites. The authors demonstrate greater potency than other bispecific antibodies and the potential to combine with other classes of agents to increase efficacy.

Targeting B-cell maturation antigen (BCMA) with chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers, or antibody drug conjugates improves outcomes in relapsed or refractory multiple myeloma, but resistance is an increasing problem, and <50% is attributable to loss of the antigen. Coffey and colleagues report on the analyses of serum and single-cell studies of bone marrow samples from patients before and after 5 days of γ-secretase inhibition (GSI) treatment prior to BCMA CAR T-cell therapy. The authors identified that GSI rapidly reduces soluble BCMA levels, increases BCMA density on myeloma cells, and alters monocyte function but does not affect CD8⁺ T-cell function, collectively indicating how GSI may reduce failure of BCMA-directed therapies.

Voso and colleagues present the largest prospective cohort of patients with acute promyelocytic leukemia originating from international multicenter clinical trials and European national registries. The authors robustly analyzed factors that influence both short-term outcomes, primarily early death and differentiation syndrome, and long-term end points. The results convincingly show that the combination of all-trans retinoic acid (ATRA) plus arsenic significantly improves outcome over ATRA plus chemotherapy, regardless of patient age and risk score, as well as highlight early death as a major ongoing challenge, especially in older patients.

In relapsed immune thrombocytopenia (ITP), the major benefit of thrombopoietin receptor agonist (TPO-RA) therapy over alternatives is the avoidance of splenectomy and strong immunosuppressive medications, with the tradeoff being the need to take a daily oral therapy or weekly injection. However, Cottu et al now show that nearly half of patients with chronic ITP who achieve a complete response to TPO-RAs for more than a year are able to safely stop therapy and remain stable for up to 4 years. These data provide an impetus for a change in practice to reduce long-term therapy in selected patients.