The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, ...and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and complete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio HR, 0.61; 95% confidence interval CI, 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups.
•The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations.•Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL.
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Sixty patients with ITP were enrolled in a phase 1–2 trial of the Bruton’s tyrosine kinase inhibitor rilzabrutinib for increasing platelet count. During 24 weeks, 40% of the patients who started ...rilzabrutinib at the 400-mg twice-daily dose had a platelet count of at least 50×10
3
per cubic millimeter. Adverse events were grade 1 or 2 and transient, with no high-grade bleeding or thrombotic events.
This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and ...progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval CI: 1.35– 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15–1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0–2 and 3–5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.
The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term ...follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7%
22.8%), muscle spasms (28.6%
11.9%), hypertension (25.5%
14.9%), atrial fibrillation/flutter (23.5%
7.9%), and pneumonia (18.4%
5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4%
34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.
Natural killer (NK) cells are key effector cells for anti-CD20 monoclonal antibodies (mAb), such as obinutuzumab and rituximab. We assessed whether low pretreatment NK-cell count (NKCC) in peripheral ...blood or tumor tissue was associated with worse outcome in patients receiving antibody-based therapy.
Baseline peripheral blood NKCC was assessed by flow cytometry (CD3
CD56
and/or CD16
cells) in 1,064 of 1,202 patients with follicular lymphoma treated with obinutuzumab or rituximab plus chemotherapy in the phase III GALLIUM trial (NCT01332968) and 1,287 of 1,418 patients with diffuse large B-cell lymphoma (DLBCL) treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP or R-CHOP) in the phase III GOYA trial (NCT01287741). The prognostic value of tumor NK-cell gene expression, as assessed by whole-transcriptome gene expression using TruSeq RNA sequencing, was also analyzed. The association of baseline variables, such as treatment arm, was evaluated using multivariate Cox regression models using a stepwise approach.
In this exploratory analysis, low baseline peripheral blood NKCC was associated with shorter progression-free survival (PFS) in both follicular lymphoma hazard ratio (HR), 1.48; 95% confidence interval (CI), 1.02-2.14;
= 0.04 and DLBCL (HR, 1.36; 95% CI, 1.01-1.83;
= 0.04), and overall survival in follicular lymphoma (HR, 2.20; 95% CI, 1.26-3.86;
= 0.0058). Low tumor NK-cell gene expression was associated with shorter PFS in G-CHOP-treated patients with DLBCL (HR, 1.95; 95% CI, 1.22-3.15;
< 0.01).
These findings indicate that the number of NK cells in peripheral blood may affect the outcome of patients with B-cell non-Hodgkin lymphoma receiving anti-CD20-based immunochemotherapy.
Cutaneous T-cell lymphomas (CTCL) represent rare non-Hodgkin lymphomas (NHL) with an incidence less than 1 per 100,000 inhabitants. The most common type of CTCL is mycosis fungoides (MF), which ...represents approximately 60% of all CTCL, followed by Sézary syndrome (SS), approximately 5%. We retrospectively analyzed the outcome of 118 patients with MF (n=96) and SS (n=22) treated between the years 1998 and 2021 at the Charles University General Hospital in Prague, Czech Republic. The ratio between men and women was 1.2:1 (62 men, and 56 women). The median age at diagnosis was 62 years (23 to 92 years). From the MF cohort 48 patients (50% out of MF cohort) presented with advanced stage disease. Ninety patients (77%) received a systemic treatment at any time from the diagnosis; the median number of therapy lines was two. At the time of database lock, the overall survival (OS) of 96 patients with MF reached 17.7 years with the median follow-up 4.0 years. With the median follow-up 2.6 years, the median OS of 22 patients with SS was 3.5 years. The most common type of systemic therapy for MF included low-dose methotrexate (61%), interferon-alpha (58%), bexarotene (28%), and chlorambucil (25%). The most common type of therapy for SS included bexarotene (64%), extracorporeal photopheresis (50%), and interferon-alpha (45%). Only the minority of patients received innovative targeted agents including brentuximab vedotin, mogamulizumab, or pembrolizumab. Besides the retrospective analysis of the CTCL cohort, current standards and future perspectives of selected innovative agents are summarized and discussed. The analyzed cohort represents the largest cohort of CTCL patients in the Czech Republic. Overall, the survival parameters of our CTCL cohort are comparable to those previously published by other groups. In conclusion, our analysis of 118 real world cohort of consecutive CTCL patients treated at the single center confirmed the efficacy of immune response modifiers and underlines the urgent need for ample implementation of innovative agents and their combinations into earlier lines of therapy.
Objectives: 90Y‐labeled anti‐CD66b monoclonal antibody clone BW 250/183 was developed for treatment of tumors. The aim of the study was the analysis of CD66 expression in lymphoproliferative ...malignancies to expand the potential of anti‐CD66‐based therapy.
Patients and methods: Bone marrow samples from 260 patients were examined for the expression of CD66 on tumor cells in 104 B‐chronic lymphocytic leukemias (B‐CLL), 28 mantle cell lymphomas (MCL), 22 follicular lymphomas (FCL), 15 marginal zone lymphomas (MZL), 12 lymphoplasmacytic lymphomas (LPL), 13 diffuse large B cell lymphomas (DLBCL), 4 T‐non‐Hodgkin lymphomas (T‐NHL), 3 B‐NHL not otherwise specified (B‐NHL NOS), 3 B acute lymphoblastic leukemias (B‐ALL), and in 56 multiple myelomas (MM) by flow cytometry.
Results: Positive (≥ 20%) expression of CD66abce clone Kat4c was detected in 76% of B‐CLL and 76.8% of MM. The highest number of CD66abce‐positive samples was in MCL and LPL (96.4% of 28 and 91.7% of 12 patients, respectively). Expression of CD66b clone BW 250/183 was examined in 114 of 260 samples. Positive expression was detected in 23.3% of B‐CLL (6/35), 17.1% of MM (7/30), and 21.4% of MCL (3/14) samples.
Conclusion: The expression of CD66b compared to CD66abce was lower in all measured samples. Use of radiolabeled anti‐CD66b antibody for the treatment of lymphoproliferative diseases appears to have limited preclinical substantiation.
The cell body space occupied by the nucleus decreased during the cell differentiation of the granulocytic cell lineage in CML (Chronic Myeloid Leukemia) patients. In contrary, in patients suffering ...from CLL (Chronic Lymphocytic Leukemia), the cell body space occupied by the nucleus during the cell differentiation of the lymphocytic lineage did not decrease despite the reduction of the cell size. Thus, the cell body space occupied by the cell nucleus during the differentiation was characteristic for each of these cell lineages.
MicroRNAs are important regulators of transcription in hematopoiesis. Their expression deregulations were described in association with pathogenesis of some hematological malignancies. This study ...provides integrated microRNA expression profiling at different phases of chronic myeloid leukemia (CML) with the aim to identify microRNAs associated with CML pathogenesis. The functions of in silico filtered targets are in this report annotated and discussed in relation to CML pathogenesis.
Using microarrays we identified differential expression profiles of 49 miRNAs in CML patients at diagnosis, in hematological relapse, therapy failure, blast crisis and major molecular response. The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR. In silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle and growth regulation as well as several key signaling pathways such as of mitogen activated kinase-like protein (MAPK), epidermal growth factor receptor (EGFR, ERBB), transforming growth factor beta (TGFB1) and tumor protein p53 that are all related to CML. Decreased levels of miR-150 were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level.
This study uncovers microRNAs that are potentially involved in CML and the annotated functions of in silico filtered targets of selected miRNAs outline mechanisms whereby microRNAs may be involved in CML pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The frequently noted visualized cell dysplastic features reflect nuclear- or nucleolar-cytoplasmic anarchy (asynchrony), premature heterochromatin condensation state, marked aneuploidy, abnormal ...nucleus-cytoplasm ratio, abnormality of cell organelles including mitochondria, abnormal presence or absence of cell lineage-specific granules, and formation of peripheral buds or blebbing on the cell surface. The cell "dysplastic" appearance is a usual expression and term widely used in clinical cytology including haematology. ...it might be very useful to use more exact terms for these cell states, because they may express different cell appearances that might be characteristic of abnormal and pathological states of the examined cell. According to the general knowledge, the large, condensed heterochromatin DNA territories express gene silencing and the RNA content in the cytoplasm reflects, to some extent, the cytoplasmic protein synthetic potential (de Robertis and de Robertis, 1987; Cremer and Cremer, 2006). ...it should be mentioned that the large size of the cell nucleus in cells with the mitotic potential should not always be considered as a cell dysplastic phenomenon, because it may just reflect the late stage of the cell cycle (Nagi, 1976).
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