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1.
ESMO Open ; 8(1): 100750, 2023 02.
Article in English | MEDLINE | ID: mdl-36634531

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is usually treated with chemoimmunotherapy in curative intention at initial diagnosis. Novel agents have improved the prognosis of high-risk patients in the front-line and relapsed setting and more accurate prognostic tools enable less intensive treatment for low-risk patients, while maintaining their good prognosis. Here, we summarize our approach to DLBCL patients in the first-line setting according to their risk profile and other common challenges in clinical practice. We recommend an abbreviated course of chemoimmunotherapy in low-risk patients and a negative interim positron emission tomography. For patients with higher-risk disease, a new combination treatment with polatuzumab vedotin has been approved and is a new option in these patients. We also discuss our approach to patients with high risk for subsequent central nervous system involvement, with leg-type lymphoma or with severe comorbidities.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Lymphoma, Large B-Cell, Diffuse , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Prognosis , Immunotherapy
2.
ESMO Open ; 6(4): 100233, 2021 08.
Article in English | MEDLINE | ID: mdl-34371380

ABSTRACT

Metastatic pheochromocytoma and paraganglioma (PPGL) are rare diseases with dismal prognosis and standard therapies are lacking. We herein report the first case of a germline anaplastic lymphoma kinase (ALK) mutation in a patient with chemorefractory metastatic pheochromocytoma in the absence of mutations of known PPGL-associated predisposing genes. Therapy with the ALK inhibitor (ALKi) brigatinib led to dramatic and durable disease remission, despite previous disease progression on the ALKi alectinib. This case underscores the potential clinical use of molecular profiling in rare diseases with limited treatment options and suggests that the ALK-R1192P point mutation might predict sensitivity to brigatinib.


Subject(s)
Adrenal Gland Neoplasms , Lung Neoplasms , Pheochromocytoma , Adrenal Gland Neoplasms/drug therapy , Adrenal Gland Neoplasms/genetics , Anaplastic Lymphoma Kinase/genetics , Austria , High-Throughput Nucleotide Sequencing , Humans , Mutation , Organophosphorus Compounds , Pheochromocytoma/diagnostic imaging , Pheochromocytoma/drug therapy , Pheochromocytoma/genetics , Pyrimidines , Registries
3.
ESMO Open ; 6(1): 100012, 2021 02.
Article in English | MEDLINE | ID: mdl-33399078

ABSTRACT

BACKGROUND: The prognosis of patients with secondary central nervous system lymphoma (SCNSL) is poor and despite massive advances in understanding the mutational landscape of primary diffuse large B-cell lymphoma (DLBCL), the genetic comparison to SCNSL is still lacking. We therefore collected paired samples from six patients with DLBCL with available biopsies from a lymph node (LN) at primary diagnosis and the central nervous system (CNS) at recurrence. PATIENTS AND METHODS: A targeted, massively parallel sequencing approach was used to analyze 216 genes recurrently mutated in DLBCL. Healthy tissue from each patient was also sequenced in order to exclude germline mutations. The results of the primary biopsies were compared with those of the CNS recurrences to depict the genetic background of SCNSL and evaluate clonal evolution. RESULTS: Sequencing was successful in five patients, all of whom had at least one discordant mutation that was not detected in one of their samples. Four patients had mutations that were found in the CNS but not in the primary LN. Discordant mutations were found in genes known to be important in lymphoma biology such as MYC, CARD11, EP300 and CCND3. Two patients had a Jaccard similarity coefficient below 0.5 indicating substantial genetic differences between the primary LN and the CNS recurrence. CONCLUSIONS: This analysis gives an insight into the genetic landscape of SCNSL and confirms the results of our previous study on patients with systemic recurrence of DLBCL with evidence of substantial clonal diversification at relapse in some patients, which might be one of the mechanisms of treatment resistance.


Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Central Nervous System , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/genetics , Clonal Evolution/genetics , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/genetics , Neoplasm Recurrence, Local/genetics
4.
Drugs Today (Barc) ; 56(3): 195-202, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32282866

ABSTRACT

Ropeginterferon alfa-2b is a novel mono-PEGylated alfa interferon. It is the first interferon approved for the treatment of patients with polycythemia vera (PV) and the first and only approved treatment for PV independent of previous hydroxyurea exposure. In contrast to other interferons, the drug has to be subcutaneously injected every 2 weeks only, with intervals of 4 weeks being possible after prolonged use. It is generally well tolerated and can lead to deep molecular responses. In this article, we provide a review of available preclinical and clinical data of ropeginterferon alfa-2b leading to its E.U. approval and give an outlook on future clinical trials involving this drug.


Subject(s)
Interferon alpha-2/therapeutic use , Interferon-alpha/therapeutic use , Polycythemia Vera/drug therapy , Polyethylene Glycols/therapeutic use , Humans , Hydroxyurea , Interferon alpha-2/administration & dosage , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use
5.
Pharmacogenomics J ; 20(2): 350, 2020 Apr.
Article in English | MEDLINE | ID: mdl-30659276

ABSTRACT

In the abstract and in other parts of the manuscript the authors wrote that the mutation rs396991 causes a valine (V) to phenylalanine (F) substitution at position 157. However, the correct codon number is 158. These errors have not been fixed in the original Article.

6.
Pharmacogenomics J ; 18(3): 474-479, 2018 05 22.
Article in English | MEDLINE | ID: mdl-28719596

ABSTRACT

FCGR2A-H131R and FCGR3A-V157F are single-nucleotide polymorphisms known to influence the outcome of patients treated with rituximab, cetuximab and trastuzumab. We investigated the impact of these polymorphisms on the clinical outcome of 103 patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with a platinum compound, fluorouracil and cetuximab as palliative first-line therapy. The survival of patients with FCGR2A-131H/H and/or FCGR3A-157V/V genotypes was significantly longer compared with patients carrying 131R and 157F alleles (median progression-free survival (PFS): 5.5 vs 4.1 months, P=0.02; median overall survival: 10.2 vs 7.2 months, P=0.04). In multivariate analysis, the FCGR2A and 3A genotypes as well as the time between initial diagnosis and relapse of disease not amenable to curative therapy remained the only independent prognostic factors for PFS. The results are in line with previous reports in colorectal cancer patients and confirm the possible value of genetic polymorphisms of immunocompetent cells for the success of cetuximab treatment.


Subject(s)
Neoplasm Recurrence, Local/drug therapy , Receptors, IgG/genetics , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Cetuximab/adverse effects , Cetuximab/genetics , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Genotype , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Polymorphism, Single Nucleotide/genetics , Progression-Free Survival , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology
8.
Leukemia ; 31(5): 1117-1122, 2017 05.
Article in English | MEDLINE | ID: mdl-27909342

ABSTRACT

Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.


Subject(s)
Hemorrhage/chemically induced , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Platelet Aggregation/drug effects , Pyrazoles/adverse effects , Pyrimidines/adverse effects , Ristocetin/pharmacology , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Drug Monitoring/methods , Female , Hemorrhage/drug therapy , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Middle Aged , Piperidines , Protein Kinase Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage
9.
Clin Oncol (R Coll Radiol) ; 26(10): 648-52, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24929649

ABSTRACT

The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Doxorubicin/analogs & derivatives , Lymphoma, Large B-Cell, Diffuse/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Female , Follow-Up Studies , Humans , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Neoplasm Staging , Polyethylene Glycols/administration & dosage , Prednisone/therapeutic use , Prognosis , Retrospective Studies , Rituximab , Survival Rate , Treatment Outcome , Vincristine/therapeutic use , Young Adult
10.
Br J Cancer ; 111(1): 55-60, 2014 Jul 08.
Article in English | MEDLINE | ID: mdl-24874478

ABSTRACT

BACKGROUND: High levels of C-reactive protein (CRP), an acute phase protein, proofed being associated with decreased clinical outcome in small-scale studies in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to evaluate the prognostic impact of pretreatment CRP levels on overall survival (OS) and disease-free survival (DFS) in a large bicentre study of DLBCL patients. METHODS: Data from 477 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian centres, were evaluated retrospectively. The prognostic influence of CRP and other factors, including age, tumour stage, and revised International Prognostic Index (R-IPI) on 5-year OS and 5-year DFS, were studied by Kaplan-Meier curves as well as univariate and multivariate Cox regression models. Influence of CRP on the predictive accuracy of the R-IPI score was determined by the Harrell concordance index. RESULTS: Kaplan-Meier curves revealed elevated CRP as a factor for decreased 5-year OS and DFS in DLBCL patients (P<0.001, log-rank test). An independent significant association between high CRP levels and poor clinical outcome in multivariate analysis for 5-year OS (HR=1.51, CI 95%=1.04-2.20, P=0.031) and for DFS (HR=1.91, CI 95%=1.28-2.85, P=0.002) was found. The estimated concordance index was 0.75 using the original R-IPI score and 0.79 when CRP was added. CONCLUSIONS: In the present study, we demonstrated high CRP levels at diagnosis of DLBCL as an independent poor prognostic factor for clinical outcome. Adding CRP to the well-established prognostic models such as the R-IPI score might improve their predictive ability.


Subject(s)
C-Reactive Protein/metabolism , Lymphoma, Large B-Cell, Diffuse/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies
11.
Strahlenther Onkol ; 190(7): 676-85, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24577133

ABSTRACT

BACKGROUND: Survival upon diagnosis of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) is highly variable and established prognostic scores do not include tissue-based parameters. METHODS: Patients who underwent neurosurgical resection as first-line therapy for newly diagnosed NSCLC BM were included. Microvascular density (MVD), Ki67 tumor cell proliferation index and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry. RESULTS: NSCLC BM specimens from 230 patients (151 male, 79 female; median age 56 years; 199 nonsquamous histology) and 53/230 (23.0%) matched primary tumor samples were available. Adjuvant whole-brain radiation therapy (WBRT) was given to 153/230 (66.5%) patients after neurosurgical resection. MVD and HIF-1 alpha indices were significantly higher in BM than in matched primary tumors. In patients treated with adjuvant WBRT, low BM HIF-1 alpha expression was associated with favorable overall survival (OS), while among patients not treated with adjuvant WBRT, BM HIF-1 alpha expression did not correlate with OS. Low diagnosis-specific graded prognostic assessment score (DS-GPA), low Ki67 index, high MVD, low HIF-1 alpha index and administration of adjuvant WBRT were independently associated with favorable OS. Incorporation of tissue-based parameters into the commonly used DS-GPA allowed refined discrimination of prognostic subgroups. CONCLUSION: Ki67 index, MVD and HIF-1 alpha index have promising prognostic value in BM and should be validated in further studies.


Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/secondary , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Ki-67 Antigen/metabolism , Microvessels/pathology , Brain Neoplasms/diagnosis , Brain Neoplasms/metabolism , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Female , Humans , Male , Middle Aged , Prevalence , Prognosis , Reproducibility of Results , Risk Factors , Sensitivity and Specificity , Survival Analysis
12.
Ann Oncol ; 25(1): 171-6, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24299961

ABSTRACT

BACKGROUND: Obesity is a well-known risk factor for the development of several types of cancer including lymphomas, but its influence on the course of disease is fairly unknown. Recently, a retrospective cancer registry analysis demonstrated significantly prolonged survival for overweight and obese patients with diffuse large B-cell lymphoma (DLBCL). The study population almost exclusively consisted of male US American patients of lower socioeconomic status and one-fifth of patients received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy without rituximab. Therefore, it remains unclear if these results can be extrapolated to the general DLBCL population. PATIENTS AND METHODS: This retrospective single-center analysis included 183 unselected DLBCL patients who were treated with rituximab and standard-dosed anthracycline-based chemoimmunotherapy as first-line therapy between January 2004 and December 2012. Patients were stratified by body mass index (BMI) into 'low BMI' (<25.0 kg/m(2)) and 'high BMI' (≥25.0 kg/m(2)). RESULTS: The two groups were well balanced regarding age, performance score, international prognostic index, B-symptoms and extranodal involvement. However, there was a trend for male sex (P = 0.053) and higher-stage disease (P = 0.066) in the high-BMI group. Patients with higher BMI had significantly longer overall survival (OS; hazard ratio [HR] 0.546; P = 0.035) with 80.9% of patients alive at 3 years versus 64.2% in the low-BMI group. BMI was also an independent prognostic factor for OS in multivariate analysis (HR 0.557; P = 0.043). CONCLUSION: We could show a significant association between overweight/obesity and improved OS in an unselected DLBCL cohort.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/pathology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Body Mass Index , Cohort Studies , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Prednisone/administration & dosage , Proportional Hazards Models , Rituximab , Treatment Outcome , Vincristine/administration & dosage , Young Adult
13.
Dtsch Med Wochenschr ; 138(41): 2093-5, 2013 Oct.
Article in German | MEDLINE | ID: mdl-24085363

ABSTRACT

HISTORY: A 77-year-old patient with a known autoimmune hemolysis for years was treated with steroids, rituximab, cyclophosphamid, cyclosporin A. Because of accompanying thrombopenia he received eltrombopag and underwent splenectomy but without lasting effect. After 3 years he presented with decreased leukocytes and worsening of thrombopenia. INVESTIGATIONS: A peripheral blood count showed moderate pancytopenia without blasts or left shift. Bone marrow biopsy revealed myelodysplasia with excessive blasts, cytogenetics showed partial trisomy 18q. TREATMENT AND COURSE: Because of the high risk of transformation to acute myeloid leukemia treatment with 5-azacytidine was started. Thrombopenia rapidly improved, but after an infectious complication treatment was paused for several months due to patient wish. Treatment was started again after 11 months because of progressive thrombopenia and resulted in a rapid hematological improvement. CONCLUSION: The new diagnosis of a myelodysplastic syndrome should be considered in the case of new cytopenia even in the presence of an already established hematological disease.


Subject(s)
Anemia, Hemolytic, Autoimmune/complications , Anemia, Hemolytic, Autoimmune/diagnosis , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/diagnosis , Purpura, Thrombocytopenic, Idiopathic/complications , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Thrombocytopenia/complications , Thrombocytopenia/diagnosis , Aged , Anemia, Hemolytic, Autoimmune/drug therapy , Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Biopsy, Needle , Bone Marrow/pathology , Diagnosis, Differential , Disease Progression , Follow-Up Studies , Humans , Leukopenia/complications , Leukopenia/diagnosis , Leukopenia/drug therapy , Male , Myelodysplastic Syndromes/drug therapy , Platelet Count , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Thrombocytopenia/drug therapy
14.
Leukemia ; 26(12): 2508-16, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22743622

ABSTRACT

Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Apoptosis/drug effects , Dactinomycin/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Tumor Suppressor Protein p53/genetics , Animals , Antineoplastic Agents/therapeutic use , Blotting, Western , Female , Flow Cytometry , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Mice , Mice, Inbred C57BL , Mice, SCID , Mice, Transgenic , Myeloid Cell Leukemia Sequence 1 Protein , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Survival Rate , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism , Vidarabine/analogs & derivatives , Vidarabine/therapeutic use
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