Emerging evidence indicates that CD4+ T cells contribute to antitumor immunity beyond their traditional roles as helpers or regulators. However, the specific subset of CD4+ T cells mediating beneficial outcomes in patients with multiple myeloma remains unclear. Here, we performed single-cell RNA sequencing and T-cell receptor sequencing on CD4+ T cells sorted from the bone marrow of patients across the stages of myeloma progression. We identified several distinct states of CD4+ cytotoxic T lymphocytes (CTLs) that were significantly increased and clonally expanded in patients with myeloma. CD4+ CTLs displayed transcriptional and phenotypic characteristics indicative of cytotoxicity, demonstrating their ability to directly kill myeloma cells. This cytotoxicity, however, was abrogated by NKG2D blockade. Notably, the abundance of NKG2D+CD4+ CTLs correlated with improved survival in patients with myeloma. Our findings suggest that harnessing CD4+ CTLs could lead to novel strategies for enhancing immunotherapy outcomes in multiple myeloma.

Jin Ju Kim, M.D., Ji Eun Jang, M.D., Hyeon Ah Lee, M.S., Mi Ri Park, B.S., Hye Won Kook, M.D., Seung-Tae Lee, M.D., Jong Rak Choi, M.D., Yoo Hong Min, M.D., Saeam Shin, M.D., and June-Won Cheong, M.D.. Ann Lab Med 2023;43:328-36. https://doi.org/10.3343/alm.2023.43.4.328

A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.

Kook HW, et al. J Korean Med Sci. 2023 Nov;39(2):e5. https://doi.org/10.3346/jkms.2024.39.e5

Background/Objectives: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders driven by somatic mutations, most commonly those in JAK2, CALR, and MPL. While conventional molecular testing often focuses on these canonical mutations, emerging data suggest that additional mutations and low-variant-allele-frequency (VAF) subclones may contribute to disease progression and prognosis. Methods: We applied ultra-deep targeted sequencing with an error-correction algorithm to analyze bone marrow and peripheral blood samples from 134 patients with essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), secondary myelofibrosis (MF), or post-MPN acute leukemia. Targeted sequencing panels were used to detect disease-associated and clonal driver mutations. Matched germline controls were not systematically available. Results: Low-VAF variants ( 5%, suggesting clonal expansion during progression. Paired sequencing at initial MPN diagnosis and leukemic transformation was available for three patients. JAK2 p.V617F VAFs differed according to treatment timing (Kruskal–Wallis test, p = 0.0138), with lower VAFs observed in untreated patients; however, this association may be influenced by treatment-selection confounding. Mutations in ASXL1 and SRSF2 were occasionally observed in ET and secondary MF, although their prognostic significance remains uncertain. Progression analyses were exploratory because of the limited number of events and longitudinally sampled patients, and formal survival or prognostic modeling was not performed. Conclusions: Ultra-deep error-corrected sequencing enables sensitive detection of low-VAF mutations in MPNs, including subclonal events potentially missed by less sensitive assays. These findings demonstrate the potential utility of high-sensitivity panel-based sequencing for molecular characterization of MPN, while larger longitudinal studies are required to establish the prognostic and clinical significance of these findings.