Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the ...strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.
Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic ...lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N=51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (P<0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA>990 pg/ml (P=0.014), sMICB>200 pg/ml (P=0.0001), and sULBP2>105 pg/ml (P<0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P=0.002), sULBP2 (P=0.002) and ZAP-70 (P=0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels>105 pg/ml were strongly associated (P=0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression.
•Baseline 18F-FDG–PET radiomics features can select patients at high risk more accurately than the IPI risk score.•The clinical PET model that was developed in the HOVON-84 data set remained ...predictive of the outcome in 6 independent studies.
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The objective of this study is to externally validate the clinical positron emission tomography (PET) model developed in the HOVON-84 trial and to compare the model performance of our clinical PET model using the international prognostic index (IPI). In total, 1195 patients with diffuse large B-cell lymphoma (DLBCL) were included in the study. Data of 887 patients from 6 studies were used as external validation data sets. The primary outcomes were 2-year progression-free survival (PFS) and 2-year time to progression (TTP). The metabolic tumor volume (MTV), maximum distance between the largest lesion and another lesion (Dmaxbulk), and peak standardized uptake value (SUVpeak) were extracted. The predictive values of the IPI and clinical PET model (MTV, Dmaxbulk, SUVpeak, performance status, and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance, using the positive predictive value (PPV). The IPI yielded an AUC of 0.62. The clinical PET model yielded a significantly higher AUC of 0.71 (P < .001). Patients with high-risk IPI had a 2-year PFS of 61.4% vs 51.9% for those with high-risk clinical PET, with an increase in PPV from 35.5% to 49.1%, respectively. A total of 66.4% of patients with high-risk IPI were free from progression or relapse vs 55.5% of patients with high-risk clinical PET scores, with an increased PPV from 33.7% to 44.6%, respectively. The clinical PET model remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.
Eertink and colleagues externally validate the clinical positron emission tomography (PET) assessment developed in the HOVON-84 trial of diffuse large B-cell lymphoma. Based on metabolic tumor volume, maximum distance between the largest lesion and another lesion, and the peak standardized uptake value, clinicalPET successfully predicted the outcomes in 6 independent studies and appeared to perform better than the international prognostic index.
Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are ...associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical-translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph+ ALL.
SPC2996 is a novel locked nucleic acid phosphorothioate antisense molecule targeting the mRNA of the Bcl-2 oncoprotein. We investigated the mechanism of action of SPC2996 and the basis for its ...clinically observed immunostimulatory effects in chronic lymphocytic leukemia (CLL). Patients with relapsed CLL were treated with a maximum of six doses of SPC2996 (0.2-6 mg/kg) in a multicenter phase I trial. Microarray-based transcriptional profiling of circulating CLL cells was carried out before and after the first infusion of SPC2996 in 18 patients. Statistically significant transcriptomic changes were observed at doses 4 mg/kg and occurred as early as 24 h after the first infusion of the oligonucleotide. SPC2996 induced the upregulation of 466 genes including a large number of immune response and apoptotic regulator molecules, which were enriched for Toll-like receptor response genes. Serum measurements confirmed the release of pro-inflammatory cytokines including chemokine (C-C motif) ligand 3 (macrophage inflammatory protein 1α) and tumor necrosis factor-α, thereby validating the in vivo transcriptomic data at the protein level. SPC2996 caused a 50% reduction of circulating lymphocytes in five of 18 (28%) patients, which was found to be independent of its immunostimulatory and anti-Bcl-2 effects.
Prognostic predictions in B-cell chronic lymphocytic leukemia (B-CLL) at early clinical stage are based on biological disease parameters, such as ZAP-70 and CD38 protein levels, genomic aberrations ...as well as immunoglobulin variable heavy chain gene (IgV(H)) mutation status. In the current study, ZAP-70 and CD38 expressions were examined by flow cytometry in 252 patients with B-CLL. Cytoplasmic ZAP-70 expression in more than 20% (ZAP-70(+)) and surface CD38 expression on more than 30% (CD38(+)) of B-CLL cells were associated with an unfavorable clinical course. The levels of ZAP-70 and CD38 did not change over time in the majority of patients where sequential samples were available for analysis. Combined analysis of ZAP-70 and CD38 yielded discordant results in 73 patients (29.0%), whereas 120 patients (47.6%) were concordantly negative and 59 patients (23.4%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70(+)CD38(+) was 30 months as compared to 130 months in patients with a ZAP-70(-)CD38(-) status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 43 months. Thus, ZAP-70 and CD38 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV(H) mutation status in B-CLL discordant for ZAP-70/CD38 pointed toward a distinct biologic background of the observed disease subgroups. This finding was also supported by microarray-based gene expression profiling in a subset of 35 patients. The expression of 37 genes differed significantly between the three groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance.
The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different ...parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca(2+) influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca(2+) increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.
Cutaneous squamous cell carcinoma (cSCC) numbers among the most common types of skin cancer and is known as one of the cancer entities with the highest mutational burden among all solid tumours. Due ...to the positive correlation between mutational burden and response rate to inhibitors of the programmed cell death 1 (PD‐1), those inhibitors are considered promising candidates for the systemic therapy of cSCC. Recently, the PD‐1 inhibitors pembrolizumab, nivolumab and cemiplimab demonstrated efficacy in the systemic treatment of locally advanced or metastatic cSCC leading to the approval of cemiplimab by the FDA (U.S. Food and Drug Administration) in 2018 and the EMA (European Medicines Agency) in 2019. Patients with haematological malignancies tend to develop skin cancers of high aggressiveness, enhanced cumulative recurrence rate and higher rates of metastases with subsequent death. Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia in the United States and Europe with the majority of patients older than 50 years of age. This neoplasm predominantly originates from B ‐cells leading to an impaired immune system of the patient. Although CLL is a B‐cell malignancy, studies have also described the involvement of T cells in the pathogenesis and progression of the disease with contradictory findings on the effects of PD‐1 inhibitors in CLL. Due to their underlying hematologic malignancy, these patients have commonly no access to PD‐1 inhibitor trials for treatment of advanced cSCC. We report on two patients with locally advanced or metastatic cSCC. Both patients had been suffering from a CLL for many years without indication for treatment. Despite a potential immunosuppressive state of the patients due to their CLL, both were treated with the PD‐1 inhibitor pembrolizumab resulting in different therapy outcomes.
Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the ...prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.
•Good response at I-PET2 and poor response at I-PET4 may qualify for randomized trials evaluating treatment de-escalation or new therapies.•The best response criterion at I-PET was ΔSUVmax, with higher discriminative power and predictive values than currently used DS4-5 criteria.
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