Blood Cancer Discovery最新文献

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.

In this issue of Blood Cancer Discovery, Pomeroy and colleagues explore a population pharmacokinetic/pharmacodynamic model of axicabtagene ciloleucel in large B-cell lymphoma, quantifying how tumor debulking before chimeric antigen receptor (CAR) T-cell infusion can significantly improve durable remission rates. Their framework incorporates mechanistic modeling principles of CAR T-cell biology and therapy, such as CAR T-cell expansion, binding, killing, and stochastic CD19 loss, providing actionable insights for optimizing combination approaches and future trial design. See related article by Pomeroy et al., p. 41.

We conducted a comparative analysis of the long-term efficacy and safety of two single-arm trials for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL): CD19/CD22-directed chimeric antigen receptor (CAR19/22) T-cell cocktail therapy alone or combined with autologous stem cell transplantation (ASCT). The study included 124 patients not in remission after bridging therapy. Cytopenia (36.92% vs. 52.54%) and infection (29.68% vs. 28.81%) were the predominant late grade ≥3 adverse events. CAR19/22 T-cell cocktail therapy combined with ASCT achieved a higher overall response rate (best overall response: 78.46% vs. 93.22%, P = 0.023) and superior progression-free survival (median, 5.68 months vs. not reached, P < 0.001) and overall survival (median, 27.61 months vs. not reached, P < 0.001) than CAR19/22 T-cell cocktail therapy alone. Independent predictors of longer progression-free survival and overall survival included achieving a complete response at 3 months and receiving combination therapy. The associations remained statistically significant after adjustment in sensitivity analyses incorporating propensity score matching and inverse probability of treatment weighting.

Significance: CAR19/22 T-cell therapy combined with ASCT significantly improves response and survival in R/R DLBCL, including high-risk patients. This approach seems to enhance the efficacy-safety balance and offers a clinically actionable strategy to optimize CAR T-cell combination therapies.

Inhibition of the tyrosine kinase BTK is a major therapeutic strategy for treating B-cell malignancies, including chronic lymphocytic leukemia (CLL). However, resistance can emerge when tumor cells acquire mutations that abrogate drug binding or when BTK activates B-cell receptor (BCR) signaling by mechanisms independent of its kinase activity. In this study, we identified upregulation of PKCβ in samples from patients with CLL resistant to BTK inhibitors (BTKi) and characterized the PKCβ inhibitor MS-553. MS-553 reduced BCR and Wnt/β-catenin signaling, overcame stromal cell mediated protection, and synergized with venetoclax in CLL samples. MS-553 also retained the cytotoxicity and inhibition of both BCR and Wnt/β-catenin signaling in models (cell lines and primary samples) of covalent BTKi-resistant (C481S BTK) and noncovalent BTKi-resistant (T474I or L528W BTK) CLL. Furthermore, MS-553 delayed disease progression and prolonged survival in the Eμ-MTCP1 murine model of CLL. Collectively our results demonstrate that selective inhibition of PKCβ has the potential to overcome BTKi-resistant CLL.

Significance: This study identified and characterized PKCβ as a therapeutic target in CLL, including CLL resistant to BTKis. Inhibition of PKCβ suppressed both BCR and Wnt/β-catenin signaling, delayed disease progression in vivo, overcame BTKi resistance mechanisms, and enhanced response to BCL-2 inhibition. See related commentary by Jebaraj and Stilgenbauer, p. 21.

Exportin-1 (XPO1/CRM1) is a validated target in hematologic malignancies best studied for its role in mediating nuclear export. In this issue of Blood Cancer Discovery, Barajas and colleagues reveal that UBTF tandem duplications found in acute myeloid leukemia complete a nuclear export sequence that enables a novel UBTF-XPO1 interaction, particularly at chromatin loci critical for leukemogenesis, thus raising the question: Could XPO1 inhibitors find new use in the UBTF-TD acute myeloid leukemia subtype? See related article by Barajas et al., p. 51.

The state of the blood cancer field and its toll on patient mortality and morbidity, adapted from the 15th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/), is presented to the US Congress and the public.

Clonal hematopoiesis of indeterminate potential, myelodysplastic syndromes, and acute myeloid leukemia are myeloid cell disorders that exist on a spectrum. Modifiable risk factors, including obesity, insulin resistance, physical activity, dietary patterns, smoking, and the microbiome, have been implicated in myeloid cell disorder pathogenesis. Although the connection between these modifiable risk factors and their association with myeloid disorders has been studied, as of September 2025, no clinical trials are ongoing that evaluate whether lifestyle interventions can alter myeloid disorder disease progression. This article reviews myeloid disorders and their association with inflammation and how lifestyle interventions may influence disease progression.

Significance: Myeloid disorders are associated with inflammation and metabolic disorders such as obesity and diabetes mellitus. Dietary and lifestyle modifications may directly influence the pathogenesis, development, and survival by addressing inflammatory and metabolic pathways. However, additional preclinical research and large prospective clinical trials are needed to confirm these findings. This review provides an overview on myeloid disorder pathogenesis and modifiable factors that influence it, which may guide future research to reduce the myeloid disorder burden and improve outcomes for patients with clonal hematopoiesis of indeterminate potential, myelodysplastic syndromes, and acute myeloid leukemia.

Resistance of chronic lymphocytic leukemia to BTK inhibitors poses a major clinical challenge; however, there is potential to overcome this obstacle by targeting the downstream protein kinase PKCβ using the novel inhibitor MS-553. By inhibiting PKCβ, MS-553 blocks B-cell receptor signaling and WNT/β-catenin and NF-κB functions, thereby inducing apoptosis in BTK inhibitor-resistant cells. See related article by Gordon et al., p. 85.