Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.

Summary. We analysed CD56 expression in 70 patients with multiple myeloma (MM) to determine its clinicopathological and prognostic significance. Fifty‐five (79%) patients were CD56⁺. CD56^– patients (n = 15) had higher β₂ microglobulin levels and a higher incidence of extramedullary disease, Bence Jones protein, renal insufficiency and thrombocytopenia than CD56⁺ patients. Their myelomas more frequently had a plasmablastic morphology. Overall survival was significantly lower in CD56^– than CD56⁺ patients (22 vs 63 months, P = 0·0002). We conclude that CD56^– MM is a discrete entity associated with more aggressive disease. The higher incidence of plasmablastic cases suggested that CD56^– MM may develop from a less mature plasma cell than CD56⁺ MM.

FOXM1 is an important cell cycle regulator and regulates cell proliferation. In addition, FOXM1 has been reported to contribute to oncogenesis in various cancers. However, it is not clearly understood how FOXM1 contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of FOXM1 in AML cells. The FOXM1 messenger RNA (mRNA) expressed in AML cell lines was predominantly the FOXM1B isoform, and its levels were significantly higher than in normal high aldehyde dehydrogenase activity (ALDH ^hi ) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G ₂ /M cell cycle arrest, a decrease in the protein expression of Aurora kinase B, Survivin, Cyclin B1, S-phase kinase-associated protein 2 and Cdc25B and an increase in the protein expression of p21 ^Cip1 and p27 ^Kip1 . FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested ( n = 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDH ^hi cells, FOXM1 gene expression was 1.65- to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AML-derived ALDH ^hi cells compared with normal ALDH ^hi cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDH ^hi cells due to inhibition of Cdc25B and Cyclin B1 expression. In summary, we found that FOXM1B mRNA is predominantly expressed in AML cells and that aberrant expression of FOXM1 induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of FOXM1 expression represents an attractive target for AML therapy.