Blood Cancer Discovery最新文献

The significant clinical benefit of bispecific T-cell engagers (TCEs) for the treatment of relapsed/refractory multiple myeloma (RRMM) may be offset by serious toxicities and treatment failure. Risk scores such as the CAR-HEMATOTOX (HTX), Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) can identify patients at risk for complications before CAR T-cell therapy, but their utility prior to TCE therapy remains elusive. We analyzed associations with outcomes and toxicities in independent discovery (n=123) and validation (n=155) cohorts treated with TCEs. Patients with HTX ≥ 3 or m-EASIX > median (> 0.86) had a significantly increased risk of prolonged hospitalization, antibiotic treatment and fever during step-up dosing. We also observed associations with cytopenias requiring therapeutic intervention, higher severe infection and intervention densities, as well as inferior response rates and reduced progression-free and overall survival. Our findings highlight the potential of these clinical scores to improve risk stratification before TCE therapy.

We explored the efficacy of the combined ibrutinib + venetoclax in patients with R/R CLL. This phase 2 study enrolled 80 patients between July 2016 and September 2018. Patients received ibrutinib for the first 3 cycles, followed by ibrutinib + venetoclax for 24 cycles. Of 79 treated patients, the median age was 61 years (IQR, 56-69); 65 (65/76, 86%) had unmutated IGHV, and 29 (37%) had either del(17p) or TP53 mutation. The median prior treatments were 1 (range, 1-3). The primary endpoint, best CR/CRi was 67%, with a bone marrow undetectable measurable residual disease (10-4 sensitivity, U-MRD4) rate of 61%. At 95.5 months median follow-up, the estimated 7-year PFS rate was 63.3%. Grade ≥3 neutropenia and thrombocytopenia occurred in 38% and 13% of patients, respectively. The 24-cycle ibrutinib + venetoclax combination led to high rates of CR/CRi and bone marrow U-MRD4 in patients with R/R CLL.

Venetoclax (VEN) combined with hypomethylating agents (HMA) improves outcomes for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, yet overall survival (OS) remains variable. We analyzed 506 AML patients treated with front-line HMA/VEN at Moffitt Cancer Center to develop a genetics-based prognostic model. In multivariate analysis, mutations in TP53, KRAS, JAK2, U2AF1, CBL and cytogenetic lesions del(7q)/-7, del(17p)/-17/i(17q), del(20q), and MECOM rearrangements predicted inferior OS, whereas IDH1/2 mutations were favorable. A point-based system stratified patients into low-, intermediate-, and high-risk groups with median OS of 54.2, 22.3, and 7.5 months, respectively, (p<0.0001; C-index 0.648). External validation (n=126) retained prognostic separation (median OS 24.7, 17.4, and 4.3 months, p=0.0005; C-index 0.626). Compared to existing HMA/VEN-specific models, our model demonstrated superior low- vs. intermediate-risk discrimination (31.9-month separation, p=0.002; HR=0.45, p=0.003), with comparable C-index. Our model supports personalized risk stratification for HMA/VEN-treated AML, pending broader validation.

Chimeric antigen receptor (CAR) T cell therapy has reshaped the therapeutic landscape for multiple myeloma (MM), yet most patients treated with BCMA-targeted CAR T cells experience disease relapse. Consequently, we sought to determine if inhibition of CD28 survival signaling could increase MM sensitivity to CAR T cell therapy. Contrary to expectations, blockade of CD28 interaction with CD80/86 accelerated tumor regrowth in preclinical MM and lymphoma CAR T therapy models. Knockout studies revealed that endogenous CD28 on 4-1BB co-stimulated CAR T cells prolonged in vivo activity, reprogrammed mitochondrial metabolism to maintain redox balance, and stimulated proliferation and release of tumor-model specific inflammatory cytokines in the tumor microenvironment. Intriguingly, transient CD28 blockade decreased levels of certain TME cytokines without significantly affecting survival of CAR T cell treated mice. Collectively, these data provide direct evidence that endogenous CD28 signaling modulates CAR T cell responses in multiple myeloma and lymphoma models.

Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 co-mutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants, and our clinic-ready diagnostic workflow, into the CMML diagnostic framework to improve accuracy.

Chimeric antigen receptor (CAR) T cells produce durable remissions in some patients with large B-cell lymphoma, but outcomes are poor in patients with large tumor burdens or limited CAR T-cell expansion. To understand these relationships and explore potential interventions, we applied established population pharmacokinetic/pharmacodynamic principles to model kinetics of axicabtagene ciloleucel (axi-cel) concentrations and tumor responses to axi-cel, and validated model outputs using independent cohorts. This mechanistic model reproduces and explains poor outcomes associated with high tumor burden and low CAR T-cell expansion, finding that proliferation of large lymphoma populations can outpace the cytotoxic effect of CAR T cells. A high ratio of lymphoma cells to CAR T cells is effectively a mechanism of CAR T-cell resistance, which could be modified by tumor debulking before infusion. This model predicts that reducing tumor burden before CAR T-cell infusion may improve durable remission rate. Future clinical studies optimizing bridging therapy may therefore enhance the success of CAR T-cell therapies.

Significance: A population pharmacokinetic/pharmacodynamic model of axi-cel in large B-cell lymphoma explains the observation that high tumor burden and low CAR T-cell expansion predict poor outcomes. This model suggests tumor debulking before CAR T infusion or deploying CAR T therapy in measurable residual disease-positive patients after first-line treatment could improve CAR T success rates. See related commentary by Altrock, p. 11.

Transcription factors and their cofactors are major and selective nononcogene dependencies in multiple myeloma cells. By performing a gain-of-function perturbation screen in human multiple myeloma cell lines, we identified the inhibitor of DNA binding (ID) genes as putative suppressors of multiple myeloma cell fitness. Among them, ID2 was found to be downregulated in multiple myeloma patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix-loop-helix factor TCF3, also known as E2A. Lower ID2 expression in multiple myeloma cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in multiple myeloma cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL6, revealing a mechanism by which the tumor microenvironment affects multiple myeloma cell behavior.

Significance: Multiple myeloma cells exploit the oncogenic and proliferative potential of TCF3 by downregulating the transcriptional regulator ID2, a process facilitated by the bone marrow microenvironment.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with limited treatment options and a poor prognosis, especially for patients refractory to standard therapies. We report the discovery of golcadomide (CC-99282), an oral cereblon-modulating CELMoD agent designed using target-specific knowledge and optimized pharmacologic properties for the treatment of DLBCL. Golcadomide exhibited rapid, deep, and sustained degradation of transcription factors IKZF1 and IKZF3, surpassing the antitumor activity of the IMiD agent lenalidomide in preclinical models. In human lymphoma cell lines, golcadomide downregulated MYC, activated IFN-stimulated genes, and promoted antiproliferation, apoptosis, and immunogenic cell death. In mouse xenografts, golcadomide preferentially distributed to tissues known to be affected by lymphoma, resulting in enhanced tumor regression and tumor-free outcomes. Pharmacologic and CRISPR screening further revealed genes and pathways underlying golcadomide's antitumor efficacy. These findings supported golcadomide as a promising drug candidate for DLBCL, providing a strong rationale for future golcadomide-based regimens.

Significance: Golcadomide is an oral cereblon-modulating agent for the treatment of DLBCL. It exhibited rapid, deep, and sustained degradation of IKZF1 and IKZF3, preferentially accumulated in lymphoma residence tissues, and delivered robust antitumor activity. These results provide a strong rationale for continued clinical investigation of golcadomide for patients with DLBCL.

Intratumoral heterogeneity and subclonal diversity, characterized by the coexistence of genetically and functionally distinct leukemic cell populations within a single patient, have long been recognized as major contributors to chemotherapy resistance and disease relapse in acute myeloid leukemia. In this issue of Blood Cancer Discovery, Karigane and colleagues delve into the mechanisms that underlie the interactions between distinct leukemic subpopulations and identify Interferon signaling as a critical regulator that determines clonal dominance and expansion. See related article by Karigane et al., p. 68.