Hideyuki Nakazawa

Dysregulation of T cell-mediated immunity is considered a major pathophysiological mechanism in acquired pure red cell aplasia (PRCA), including idiopathic PRCA, large granular lymphocytic leukemia-associated PRCA, and thymoma-associated PRCA. Although STAT3 mutations are frequently detected in PRCA patients, the roles of other mutational profiles and their impact on clinical characteristics remain unclear. In this study, whole-exome sequencing and targeted sequencing using a custom-designed panel were performed on 53 PRCA patients. The most frequently mutated genes were STAT3 (36%), PCLO (9%), TET2 (9%), NEB (6%), DNMT3A (6%), and POT1 (6%). Based on genetic profiles, patients were classified into three groups: those with STAT3 variants (group S), those without STAT3 variants but with variants in clonal hematopoiesis (CH)-related genes (group C), and those without variants in either STAT3 or CH-related genes (group O). Patients in group C had a higher median age compared to group S, while group S exhibited milder anemia severity than group C. Additionally, POT1 variants were associated with the idiopathic subtype of PRCA in females, often co-occurring with STAT3 variants. Variants in CH-related genes and other genes, including STAT3 and POT1, may play crucial roles in the pathophysiology of PRCA.

Fludarabine and myeloablative busulfan (FluBu4) in allogeneic hematopoietic stem cell transplantation (HSCT) for older people have not been adequately examined. This retrospective study analyzed data from a large‐scale, nationwide database in Japan. Adult patients (> 15 years old, y/o) who received their first HSCT with FluBu4 for hematological malignancies were included. They were categorized into the younger (< 60 y/o, N = 1295) and the older group (≥ 60 y/o, N = 993). The 3‐year overall survival (OS) rate after HSCT was significantly worse in the older group than in the other (p < 0.01, 39.9% vs. 48.5%). The 3‐year non‐relapse mortality (NRM) was significantly higher in the older group than in the other (p < 0.01, 30.9% vs. 23.0%), and the 3‐year cumulative incidence of relapse was comparable between them. According to the multivariate analysis, age ≥ 60 years was significantly associated with poor OS and high NRM. In a subgroup analysis of the older group, the use of additional chemotherapeutic drugs to FluBu4 was significantly associated with poor OS and high NRM. Total body irradiation was significantly associated with high NRM and 1‐year incidence of sinusoidal obstruction syndrome but not with OS. Thus, FluBu4 should be used with caution in older people.

Summary: The graft‐versus‐lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non‐Hodgkin lymphomas (NHLs; indolent B‐NHLs, n = 689; aggressive B‐NHLs, n = 720; mature T/NK‐NHLs, n = 795) receiving a first allo‐HSCT in 2003–2017. Pre‐transplant lymphoma control showed complete response (CR) in 759 and non‐CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I‐II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43–0.91), especially in mature T/NK‐NHL (HR, 0.46; 95% CI, 0.26–0.83) and extensive cGVHD in patients with mature aggressive B‐NHLs (HR, 0.55; 95% CI, 0.31–0.97). In total, limited cGVHD was associated with superior survivals (progression‐free survival: HR, 0.71; 95% CI, 0.56–0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre‐transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed.

Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established three ANKL-patient-derived xenograft mice (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a non-canonical hematopoietic organ in adults, serves as a principal niche for ANKL, and that inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.

Leukemia may rarely develop in a woman during pregnancy, posing clinical challenges to the patient, fetus, family, and medical staff managing malignancy and pregnancy. We retrospectively analyzed cases of pregnancy-associated leukemia consecutively diagnosed and treated at a local tertiary-care hospital in Nagano, Japan, over the past 20 years. Five cases were identified among 377,000 pregnancies in the area (one in every 75,000 pregnancies), all involving acute leukemia (three acute myelogenous leukemia [AML] and two acute lymphoblastic leukemia [ALL]). The cases were diagnosed in the first trimester (n = 1), second trimester (n = 3), or third trimester (n = 1). There were no apparent pregnancy-associated delays in diagnosing and treating the cases. Three patients underwent induction chemotherapy during pregnancy, two of whom eventually delivered healthy babies. One of the five patients chose abortion before chemotherapy initiation. Two cases showing high-risk features at the diagnosis (AML with an FLT3-ITD mutation [n = 1] and relapsed ALL [n = 1]) eventually died despite consolidative allogeneic hematopoietic stem cell transplantation. Our results suggested that patients with pregnancy-associated acute leukemia can be treated similarly to nonpregnant patients, although pregnancy imposes particular clinical challenges that should be resolved with multidisciplinary care.

Supplementary Table from Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia