Background: We aimed to validate a simple Comprehensive Geriatric Assessment (CGA) in older adults with diffuse large B-cell lymphoma (DLBCL) in China and to evaluate the tolerability and efficacy of CGA-driven therapy. Materials and Methods: In total, 78 patients with DLBCL aged ≥60 years were evaluated using CGA with the following parameters: age ≥ 80 years, activities of daily living (ADL), instrumental ADL, and modified cumulative illness rating score for geriatrics. Patients were grouped as fit, unfit, or frail. Patients classified as fit received standard-dose rituximab plus CHOP, whereas patients in the latter two groups received reduced-dose or reduced-agent therapy. The overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and toxicities in the three groups were evaluated. Results: According to the CGA, 45 (57.5%) patients were classified as fit, 5 (6.4%) as unfit, and 28 (35.9%) as frail. The ORR was 82.1% (64/78) among all the patients, including 55 patients (70.6%) who achieved complete response and 9 patients (11.5%) who achieved partial response. In the fit and unfit + frail groups, it achieved 97.8% and 60.6%, respectively. In total, 26 (33.3%) patients (10/45 [22.2%] fit and 16/33 [48.5%] unfit + frail) showed disease progression or recurrence. The median follow-up time was 18 months (range, 5–62). The 3-year OS and PFS rates were 82% and 58%, respectively. There were no treatment-related deaths. Conclusion: A simple CGA in older adults with DLBCL may be an effective tool for guiding therapeutic strategies in China. Implications for Practice: Diffuse large B-cell lymphoma (DLBCL) is the most common malignant lymphoma in older adults. The simple tool, Comprehensive Geriatric Assessment (CGA), is proved to be an effective method to identify older adults with DLBCL who are suitable for standard-dose R-CHOP regimen therapy. This is the first prospective trial in China to evaluate the tolerability and efficacy of CGA-driven therapy for older adults with DLBCL, and the result showed that this simple CGA may be an effective tool for guiding therapeutic strategies.

Background: We aimed to validate and refine the Age, Comorbidities, and Albumin (ACA) index in elderly Chinese patients with diffuse large B-cell lymphoma (DLBCL) and propose a more effective method for comprehensive geriatric assessment (CGA). Materials and Methods: Patients ≥65 years of age who had been diagnosed with de novo DLBCL in the Institute of Hematology, Beijing Hospital, were screened for eligibility (n = 99). Results: Based on the ACA index, 39, 31, 26, and 3 patients were categorized into the “excellent,” “good,” “moderate,” and “poor” groups, respectively. The 2-year treatment-related mortality rate was significantly higher and the survival rates poorer in the ACA “moderate to poor” group compared with those of the ACA “good” and “excellent” groups. Multivariable model analysis identified two independent predictors of overall survival: the instrumental activities of daily living (IADL) scale and the ACA index. IADL scores of 6 to 7 and the ACA “good” group were assigned 1 point; IADL scores ≤5 and the ACA “moderate to poor” group were assigned 2 points. Based on these data, we created a three-category system (IADL ACA index [IACA index]): low risk, score 0; intermediate risk, score 1 to 2; and high risk, score 3 to 4. The IACA index could effectively discriminate the response rates, overall survival, and progression-free survival rates in elderly patients with DLBCL. Conclusion: We observed that the ACA index could partially predict the clinical outcomes of elderly DLBCL patients in China. Based on this index, we proposed the IACA index as an effective tool for CGA in DLBCL. Implications for Practice: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent types of malignant lymphoma in elderly people, and identifying patients suitable for curative therapy is critical in the improvement of clinical outcomes. Recently, some authors proposed the Age, Comorbidities, and Albumin (ACA) index. Combining the use of the instrumental activities of daily living (IADL) scale and the ACA index, this article describes the IADL ACA index (IACA index), which is an effective tool for comprehensive geriatric assessment in DLBCL.

Purpose: The purpose of this study was to investigate the remodeling of the multiple myeloma microenvironment after B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T (CAR-T) cell therapy. Experimental Design: We performed single-cell RNA sequencing on paired bone marrow specimens (n = 14) from seven patients with multiple myeloma before (i.e., baseline, “day −4”) and after (i.e., “day 28”) lymphodepleted BCMA CAR-T cell therapy. Results: Our analysis revealed heterogeneity in gene expression profiles among multiple myeloma cells, even those harboring the same cytogenetic abnormalities. The best overall responses of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells, enhanced CD8+ effector T-cell cytotoxic activity, and elevated type 1 conventional dendritic cell (DC) antigen presentation ability. DC re-clustering inferred intramedullary-originated type 3 conventional DCs with extramedullary migration. Cell–cell communication network analysis indicated that BCMA CAR-T therapy mitigates BAFF/GALECTIN/MK pathway–mediated immunosuppression and activates MIF pathway–mediated anti–multiple myeloma immunity. Conclusions: Our study sheds light on multiple myeloma microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.

Background: Multiple myeloma (MM) is the second most common hematological malignancy that still lacks effective clinical treatments. In particular, MM with central nervous system (CNS) invasion occurs rarely. Although B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T (CAR-T) cell therapy has shown great promise for the treatment of relapsed/refractory MM, few studies have reported whether BCMA CAR-T could inhibit MM with CNS invasion. Case Presentation: In this study, we report a special case of a 63-year-old male patient who suffered MM with CNS invasion and presented rapid extramedullary disease (EMD) progression into multiple organs. Before CAR-T cell infusion, this patient received five cycles of bortezomib, Adriamycin, and dexamethasone (PAD) and an autologous transplant as the front-line treatment, followed by two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) as the second-line regimen, and daratumumab, bortezomib, dexamethasone (DVD) as the third-line regimen. Since the patient still showed rapid progressive disease (PD), BCMA CAR-T cells were infused, and 1 month later, a stringent complete response (sCR) was achieved, and the response lasted for 4 months. Meanwhile, only grade 1 cytokine release syndrome (CRS) was observed. Conclusion: This case report demonstrated that BCMA CAR-T could effectively eradicate CNS-involved MM with low adverse events, suggesting that CAR-T cell therapy could be a feasible therapeutic option for this kind of refractory disease. Clinical Trial Registration: https://ClinicalTrials.gov, identifier: NCT04537442.a

Background Chimeric antigen receptor (CAR)-T cell has revolutionary efficacy against relapsed/refractory multiple myeloma (R/R MM). However, current CAR-T cell therapy has several limitations including long vein-to-vein time and limited viability. Methods A 4-1BB-costimulated B-cell maturation antigen (BCMA) CAR-T integrating an independently-expressed OX40 (BCMA-BBZ-OX40) was designed and generated by a traditional manufacturing process (TraditionCART) or instant manufacturing platform (named InstanCART). The tumor-killing efficiency, differentiation, exhaustion, and expansion level were investigated in vitro and in tumor-bearing mice. An investigator-initiated clinical trial was performed in patients with R/R MM to evaluate the outcomes of both TraditionCART and InstanCART. The primary objective was safety within 1 month after CAR-T cell infusion. The secondary objective was the best overall response rate. Results Preclinical studies revealed that integrated OX40 conferred BCMA CAR-T cells with superior cytotoxicity and reduced exhaustion levels. InstanCART process further enhanced the proliferation and T-cell stemness of BCMA-BBZ-OX40 CAR-T cells. BCMA-BBZ-OX40 CAR-T cells were successfully administered in 22 patients with R/R MM, including 15 patients with TraditionCART and 7 patients with InstanCART. Up to 50% (11/22) patients had a high-risk cytogenetic profile and 36% (8/22) had extramedullary disease. CAR-T therapy caused grade 1–2 cytokine release syndrome in 19/22 (80%) patients, grade 1 neurotoxicity in 2/22 (9%) patients and led to ≥grade 3 adverse events including neutropenia (20/22, 91%), thrombocytopenia (15/22, 68%), anemia (12/22, 55%), creatinine increased (1/22, 5%), hepatic enzymes increased (5/22, 23%), and sepsis (1/22, 5%). The best overall response rate was 100%, and 64% (14/22) of the patients had a complete response or better. The median manufacturing time was shorter for InstanCART therapy (3 days) than for TraditionCART therapy (10 days). Expansion and duration were dramatically higher for InstanCART cells than for TraditionCART cells. Conclusions BCMA-BBZ-OX40 CAR-T cells were well tolerated and exhibited potent responses in patients with R/R MM. InstanCART shortened the manufacturing period compared to TraditionCART, and improved the cellular kinetics. Our results demonstrated the potency and feasibility of OX40-modified BCMA CAR-T cells using InstanCART technology for R/R MM therapy. Trial registration number This trial was registered at www.clinicaltrials.gov as #NCT04537442.

THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies.