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Background. Tyrosine kinase inhibitors could treat chronic myelogenous leukemia (CML) effectively, but they have no effect on patients with T315I mutation. It is necessary to find drugs to overcome the resistance. Quercetin (Qu) is a kind of bioflavonoid with an antitumor effect. In this study, we observed the effect of Qu on proliferation and Wnt/β-catenin pathway in KBM7R cells, an imatinib-resistant cell with T315I mutation. Methods. The IC50 of Qu was detected by trypan blue staining. The KBM7R cell apoptosis and cycle were detected through the method of flow cytometry (FCM). The expression of the related mRNA and protein was evaluated by means of an RT-PCR assay and western blot in KBM7 (sensitive to IM) and KBM7R cells. Results. These results showed that in the KBM7R cell, the proliferation inhibition effect was increased after 48 h administration with different Qu concentrations. The IC50 to Qu was 241.7 μmol/L. The different doses of Qu (50, 100, and 200 μmol/L) would raise apoptosis and depress the cell cycle at the G1 phase. Dealing with a median Qu concentration (100 μmol/L) for 48 h, the mRNA and the protein level of caspase-3, caspase-8, and caspase-9 along with p21 and p27 raised compared with the control. The median concentration of Qu could inhibit both the mRNA and protein levels of GSK-3β, β-catenin, and Lef-1 in the Wnt/β-catenin signal pathway and also the downstream targets PPAR-δ and cyclin D1 in both KBM7 and KBM7R cells. Conclusions. Our findings suggest that Qu could inhibit proliferation, induce apoptosis, and arrest the cell cycle on IM-resistant KBM7R cells with T315I mutation. And this effect could be related with the inhibition of the Wnt/β-catenin signal pathway and downstream targets.

Tyrosine kinase inhibitors could treat chronic myelogenous leukemia (CML) effectively, but they have no effect on patients with T315I mutation. It is necessary to find drugs to overcome the resistance. Quercetin (Qu) is a kind of bioflavonoid with an antitumor effect. In this study, we observed the effect of Qu on proliferation and Wnt/The ICThese results showed that in the KBM7R cell, the proliferation inhibition effect was increased after 48 h administration with different Qu concentrations. The ICOur findings suggest that Qu could inhibit proliferation, induce apoptosis, and arrest the cell cycle on IM-resistant KBM7R cells with T315I mutation. And this effect could be related with the inhibition of the Wnt/

Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin B-cell lymphoma and therapeutic options of MCL are limited. We conducted a real-world, multicenter study enrolled 1261 MCL patients from nine medical centers in China to evaluate patients’ outcomes.Methods: This retrospective study enrolled 1261 adult MCL patients between January 2000 and December 2020 from nine medical centers in China. Patients’ characteristics, treatment and survival outcomes were evaluated. Results:145 patients (11%) received Bruton’s tyrosine kinase inhibitors (BTKi)-containing regimens as frontline therapy. 12% of the younger patients received autologous hematopoietic stem cell transplantation (AHCT) consolidation. The estimated 2-year progression-free survival (PFS) and 5-year overall survival (OS) rate from the initiation of front-line treatment for the entire cohort was 62.4% and 57.2% respectively. Age≥65 years, high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI), Ki-67>30% and blastoid/pleomorphic histology were associated with shorter PFS or OS. For younger patients, induction therapy with BTKi-containing regimens yield similar efficacy in 3-year PFS and OS as compared to the standard high-dose immunochemotherapy with AHCT (65.5% vs 66.6%, p=0.907 and 84.8% vs 92.3%, p=0.204). For the relapsed or refractory MCL patients in this cohort, the 5-year OS from the initiation of salvage therapy was 36.0%. A total of 23 patients developed hepatitis B virus (HBV) reactivation after immunochemotherapy, while BTKi treatment was not associated with higher rate of HBV reactivation. Conclusions:In conclusion, for younger Chinese MCL patients, the addition of BTKi in frontline therapy is a safer and more convenient alternative treatment strategy. For MCL patients with resolved hepatitis B, anti-HBV prophylaxis should not be neglected.

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton's tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL.

The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL). Most DHL patients present with Ann Arbor's stage III/IV, a comparatively higher rate of extranodal involvement including bone marrow and central nervous system infiltration, high levels of lactate dehydrogenase, and an elevated Ki67 expression in the tumor cells. Newer therapeutic approaches, including targeted therapy against BCL2, MYC, or other associated pathways, are needed. In addition, recent therapies that harness the immune system, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, are changing the paradigm of treatment for non-Hodgkin lymphoma and could impact the outcome of DHL.

Background Spontaneous regression has been reported in some indolent forms of lymphoma. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm and has a poor prognosis. However, approximately 30% of MCL patients can exhibit indolent clinical behavior. To date, complete spontaneous regression of MCL has not been reported. Case presentation We describe four cases of spontaneous regression of MCL. At the time of presentation, these patients were asymptomatic, with lymph node enlargement and mild to moderate fluorodeoxyglucose (FDG) uptake on FDG-positron emission tomography combined with computed tomography. One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity, which may have a role in the clearance of tumor cells. Conclusions In this report, we support the use of a “wait and watch” strategy for MCL patients with no risk factors and indolent behavior. This strategy helps spare patients from further potentially harmful chemotherapy. In addition, we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low-volume disease.