Showing papers by "Jana Markova published in 2017"
University of Cologne1, VU University Medical Center2, Charles University in Prague3, Heidelberg University4, University of Duisburg-Essen5, University of Tübingen6, Innsbruck Medical University7, University of St. Gallen8, Technische Universität München9, Charité10, Ludwig Maximilian University of Munich11, Robert Bosch Hospital12
TL;DR: This open-label, randomised, parallel-group phase 3 trial investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it forPET- 2-negative patients and showed non-inferiority in the 5-year progression-free survival estimates.
250 citations
TL;DR: This open-label, international, randomised, phase 3 study aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy.
Abstract: Summary Background Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. Methods In this open-label, international, randomised, phase 3 study, we recruited patients aged 18–60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5–8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25–42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0–95·7) for patients in the BEACOPP escalated group and 93·0% (89·4–96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI −4·0 to 7·3; log rank p=0·99). Common grade 3–4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one ( escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. Interpretation The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Funding Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.
75 citations
01 Dec 2017
TL;DR: This updated analysis of the HD15 trial confirms the efficacy and reports on the long-term safety of a shortened first-line chemotherapy consisting of 6xeBEACOPP followed by PET-guided radiotherapy in advanced-stage HL.
Abstract: The international, randomized phase 3 HD15 trial established 6xeBEACOPP as standard therapy for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) within the German Hodgkin Study Group (GHSG). We performed a follow-up analysis to assess long-term efficacy and safety of this approach. Between 2003 and 2008, 2182 patients aged 18 to 60 years were recruited and randomized in a 1:1:1 ratio between 8 or 6 cycles of eBEACOPP or 8 cycles of the dose-dense BEACOPP-14 regimen, each followed by 30 Gy radiotherapy in case of positron emission tomography (PET)-positive residual lesions ≥2.5 cm. The study aimed at demonstrating non-inferiority regarding efficacy of the 2 experimental arms on a significance level of 2.5% each. The intention-to-treat analysis comprised 2126 patients with a median follow-up of 102 months. Ten-year progression-free survival was 81% (97.5% CI 77-85) with 8xeBEACOPP, 84% (80-87) with 6xeBEACOPP, and 84% (80-87) with 8xBEACOPP-14; the non-inferiority margin of 1.51 for the hazard ratio (HR) could be excluded for both comparisons (6xeBEACOPP, HR = 0.7, 97.5% CI 0.5-1.0; 8xBEACOPP-14, HR = 0.9, 97.5% CI 0.7-1.2). Overall survival at 10 years was 88% (85-91), 90% (88-93), and 92% (89-94), respectively. A total of 142 second malignancies corresponding to 10-year cumulative incidences of 10%, 7%, and 7% and standardized incidence ratios of 4.3, 2.5, and 2.8 were reported for 8xeBEACOPP, 6xeBEACOPP, and 8xBEACOPP-14, respectively. This updated analysis of the HD15 trial thus confirms the efficacy and reports on the long-term safety of a shortened first-line chemotherapy consisting of 6xeBEACOPP followed by PET-guided radiotherapy in advanced-stage HL.
44 citations
TL;DR: Survivors after initially successful therapy for cHL are at an 85-fold risk for recurrence of disease compared with the general German population and regular clinical follow-up is recommended for timely detection of LR-HL.
Abstract: PurposeClinical characteristics, therapeutic approaches, and prognosis of late relapse (LR) in patients with classic Hodgkin lymphoma (cHL) are poorly understood. We performed a comprehensive analysis of LR of Hodgkin lymphoma (LR-HL).MethodsTo estimate the incidence of LR-HL, we retrospectively analyzed 6,840 patients with cHL included in the German Hodgkin Study Group trials HD7 to HD12. Patients who experienced a relapse > 5 years into remission were compared with patients in continued remission for > 5 years and with those who experienced a relapse ≤ 5 years after first diagnosis.ResultsWith a median observation time of 10.3 years, 141 incidences of LR-HL were observed. Cumulative incidences at 10, 15, and 20 years rose linearly and were 2.5%, 4.3%, and 6.9%, respectively. The standardized incidence ratio for HL with respect to age- and sex-matched German reference data was 84.5 (95% CI, 71.2 to 99.7). LR-HL was more frequently observed in patients with early-stage favorable than unfavorable or advanc...
23 citations
TL;DR: This study provides the evidence that cHL can be genotyped by using plasma cfDNA as source of tumor DNA, pointed to a non‐overlapping genotype between newly diagnosed and refractory cases, and identified ITPKB as a new gene specifically involved in ~30% of cHL patients.
Abstract: By pathway analysis, the mutational profile pointed to the involvement of PI3K/AKT signaling, cytokines signaling, NF‐kB signaling and immune escape in cHL. ITPKB (a negative regulator of PI3K) was specifically mutated in cHL across aggressive B cell lymphomas. In RS cells from wild type cases, the ITPKB protein showed a nucleo‐cytoplasmic pattern. Conversely, in RS cells from mutated cases, ITPKB localized only in the cytoplasm, pointing to a functional impact of mutations on the subcellular localization of the protein. Consistent with the involvement of ITPKB in PI3K signaling, the L‐1236 cHL cell line, that harbored a truncating mutation of ITPKB, was resistant to PI3K inhibitors (RP6530 and AEZS136). Conversely, cHL cell lines harboring a wild type ITPKB (L‐540, L‐428, KM‐H2) maintained sensitivity to these compounds (Figure 1D). Conclusions: This study provides the evidence that cHL can be genotyped by using plasma cfDNA as source of tumor DNA, pointed to a non‐overlapping genotype between newly diagnosed and refractory cases, and identified ITPKB as a new gene specifically involved in ~30% of cHL patients.
6 citations
TL;DR: Many clinical risk factors were associated with an unfavorable iDS, including adverse performance status, high international prognostic score (IPS) and the presence of large mediastinal mass (LMM), extranodal disease, 3 or more nodal areas and elevated ESR.
3 citations
TL;DR: This dissertation aims to provide a history of nuclear medicine in the Czech Republic and its applications in the context of oncocytogenetics and cancer research.
Abstract: Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic; Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Prague, Czech Republic; 9 Institute of nuclear medicine, Charles University General Hospital in Prague, Prague, Czech Republic; 10 Institute of Pathology, Charles University Hospital and First Faculty of Medicine, Prague, Prague, Czech Republic
1 citations
TL;DR: Hodgkin's lymfom (HL) as mentioned in this paper is vylecitelne nadorove onemocněni u 80 % až 90 % mladsich pacients, but prognoza starsich pacienti představuji 10-20 % of HL.
Abstract: Hodgkinův lymfom (HL) je vylecitelne nadorove onemocněni u 80 % až 90 % mladsich pacientů, ale prognoza starsich pacientů
nad 60 let je výrazně horsi. Starsi pacienti představuji 10–20 % ze vsech připadů HL. V důsledku horsiho celkoveho zdravotniho
stavu a dalsich přidružených onemocněni je jejich tolerance chemoterapie výrazně nižsi ve srovnani s mladsimi pacienty s nutnosti
redukce davek chemoterapie. Na zakladě literarnich udajů a dat z ceskeho registru HL jsou v clanku shrnuty doporuceni lecby,
možna toxicita a prognoza pacientů v seniorskem věku. V soucasnosti se i u starsich pacientů zkousi nove leky samostatně nebo
v kombinaci s chemoterapii s cilem zvýsit ucinnost a omezit nežadouci ucinky lecby.