Hematological Oncology最新文献

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/β-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/β-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/β-catenin pathway with the CBP/β-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and β-catenin while upregulating GSK-3β expression. The interaction between Hh/GLI1 and Wnt/β-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of β-catenin and decreased the inhibition of GSK-3β in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/β-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

The overall prognosis of older patients with acute myeloid leukemia (AML) is dismal. Only a small subgroup experiences long-term survival. The discrimination between patients who are candidates for potentially curative approaches and those who are not is crucial since - in addition to differences in terms of AML-directed treatment - different policies concerning intensive care unit (ICU) admission and involvement of specialized palliative care (SPC) seem obvious. To shed more light on characteristics, outcomes and health care utilization of older individuals with AML, we conducted an analysis comprising 107 consecutive patients with newly diagnosed AML aged ≥70 years treated at an academic tertiary care center in Germany between 1 January 2015, and 31 December 2020. Median age was 75 years (range: 70–87 years); 45% of patients were female. The proportion of patients receiving intensive induction chemotherapy was 35%, 55% had low-intensity treatment and 10% did not receive AML-directed treatment or follow-up ended before treatment initiation. At least one ICU admission was documented for 47% of patients; SPC was involved in 43% of cases. Median follow-up was 199 days. The median overall survival (OS) was 2.5 months; the 1-year OS rate was 16%. Among patients who died during observation, the median proportion of time spent in the hospital between AML diagnosis and death was 56%. The most common places of death were normal wards (31%) and the ICU (28%). Patients less frequently died in a palliative care unit (14%) or at home (12%). In summary, results of the present analysis confirm the unfavorable prognosis of older patients with AML despite intensive health care utilization. Future efforts in this patient group should aim at optimizing the balance between appropriate AML-directed treatment on the one hand and health care utilization including ICU stays on the other hand.

Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.

Involvement of female genital track (FGT) by diffuse large B cell lymphoma (DLBCL) represents an extremely rare diagnosis. Especially data regarding early-stage disease (i.e., IE, IIE) is very limited. Importantly, previous studies showed controversial results about the risk of central nervous system (CNS) relapse in this entity. Herein, we describe one of the largest reported real-world series of patients with early-stage FGT DLBCL aiming to investigate the clinicopathological characteristics, response to therapy and survival outcomes in the era of immunochemotherapy. We analyzed 21 consecutive patients with biopsy proven DLBCL from uterus or ovary classified as stage IE or IIE out of 1905 newly diagnosed DLBCL patients (1.1%). Uterine and ovarian localization was observed in 14 and seven patients, respectively. Median age was 66 years (range 33–96); 9/21 (43%) were <55 years. Regarding Cell of Origin DLBCL subtype, Germinal Center B-cell subtype was found in seven patients, non-GCB in 10 and non-classified in 4 patients. Median follow-up was 57 months and 5-year overall survival, lymphoma specific survival and Freedom from Progression were 78%, 89% and 90%, respectively. There was no correlation of patients' characteristics with survival parameters. Interestingly, none of the patients experienced CNS relapse. Our results indicate that localized FGT DLBCL exhibits a good prognosis and may not increase the risk for secondary CNS involvement.

Biomarkers for immune checkpoint inhibitors (ICIs) response and resistance include PD-L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest especially in lymphomas. To explore the potential role of GM in this clinical issue, feces of 30 relapsed/refractory lymphoma (Hodgkin and primary mediastinal B-cell lymphoma) patients undergoing ICIs were collected from start to end of treatment (EoT). GM was profiled through Illumina, that is, 16S rRNA sequencing, and subsequently processed through a bioinformatics pipeline. The overall response rate to ICIs was 30.5%, with no association between patients clinical characteristics and response/survival outcomes. Regarding GM, responder patients showed a peculiar significant enrichment of Lachnospira, while non-responder ones showed higher presence of Enterobacteriaceae (at baseline and maintained till EoT). Recognizing patient-related factors that may influence response to ICIs is becoming critical to optimize the treatment pathway of heavily pretreated, young patients with a potentially long-life expectancy. These preliminary results indicate potential early GM signatures of ICIs response in lymphoma, which could pave the way for future research to improve patients prognosis with new adjuvant strategies.

To retrospectively analyze whether the second revision of the international staging system (R2-ISS) influenced prognosis at treatment initiation in patients with multiple myeloma (MM) receiving anti-CD38 antibody-based triplet treatments. High-risk chromosomal abnormalities were examined from diagnosis to treatment initiation and considered positive if detected once. R2-ISS was recalculated at the initiation of treatment and defined as “dynamic R2-ISS." Data from 150 patients who underwent the defined treatments were analyzed. The median progression-free survival (PFS) was 19.5 months, and the median overall survival (OS) was 36.5 months. Dynamic R2-ISS significantly stratified prognoses for both PFS and OS. The median PFS for patients with dynamic R2-ISS IV was 3.3 months, and the median OS was 11.7 months, indicating extremely poor outcomes. Although the Revised International Staging System (R-ISS) calculated at the initiation of treatment significantly stratified treatment outcomes, the patients classified as R-ISS could be further stratified by R2-ISS to provide better prognostic information. Dynamic R2-ISS showed potential as a prognostic tool in patients with MM who are treated with anti-CD38 antibody-based triplet therapies.

Previous research has demonstrated that the combination of Venetoclax (Ven) and intensive chemotherapy (IC) enhances the complete response (CR) and minimal residual disease (MRD) negative rate in patients with de novo Acute Myeloid Leukemia (AML).^1-5 Our previous study showed that Ven combined with DA (2 + 6) is a highly effective and safe induction therapy for AML patients.¹ The objective of this data update is to further substantiate the efficacy and safety of this induction regimen.

Until 30 Nov 2023, 85 patients were enrolled in this study. Baseline characteristics of 85 patients are in Table S1. According to the ELN 2022 risk classification, 37 (43.5%), 13 (15.3%), and 35 (41.2%) patients belonged to the favorable, intermediate, and adverse groups, respectively.

After one cycle induction therapy, the overall response rate (ORR, CR + CRi + PR) was 94.1% (80/85) with a composite complete response rate (cCR, CR + CRi) of 91.8% (78/85) and 85.7% (60/70) of the patients reached cCR with MRD (−) by flow cytometry. The cCR rate was 97.3% (36/37) in patients with ELN (2022) favorable risk, 84.6% (11/13) in patients with intermediate risk, and 88.6% (31/35) in patients with adverse risk (Table 1). The adverse effects and recovery time of blood cells consistent with our previous reports. Tumor lysis syndrome was only observed in one patient, and one patient died during induction therapy.

Until 30 Jan 2024, with a median follow-up of 12 (0.5–24) months, eleven (11/84, 13.1%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). The estimated 12-month overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) rates were 82.2%, 81.9%, 82.7%, respectively (Figure S1). According to the 2022 ELN prognostic risk classification, the estimated 12-month OS, EFS, and DFS rates were 93.5% (95% CI: 88.3%–98.6%), 93.3% (95% CI: 88.1%–98.5%), and 93.3% (95% CI: 84.3%–100%), respectively, in favorable risk group; 91.7% (95% CI: 86.6%–96.8%), 90.0% (95% CI: 84.7%–95.3%), 90.9% (95% CI: 73.8%–100%), respectively, for intermediate-risk patients; and 64.6% (95% CI: 44.4%–84.8%), 62.9% (95% CI: 41.9%–83.9%), and 64.9% (95% CI: 43.7%–86.1%), respectively for adverse-risk patients (Figure 1).

Our previous study showed that Ven combined with DA (2 + 6) is a highly effective and safe induction therapy. To further corroborate our previous results, we extended the study to continue enrolled patients and continue follow-up of earlier patients.

The updated results are shown that the ORR after one cycle of induction was 94.1% (80/85) with a cCR rate of 91.8% (78/85) and MRD (−) rate 85.7%. The rates of cCR, MRD negativity, and recovery time for neutrophils and PLT counts were consistent with our previous report. The results further substantiate the efficacy and safety of our induction regimen. In comparison to previous reports,^{2, 4, 5}