Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.
- MeSH
- centrální nervový systém patologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- lymfom z plášťových buněk * patologie MeSH
- pyrazoly škodlivé účinky MeSH
- pyrimidiny MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
INTRODUCTION: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts. PATIENTS AND METHODS: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310). RESULTS: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry). CONCLUSION: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.
- MeSH
- chemorezistence genetika MeSH
- difúzní velkobuněčný B-lymfom farmakoterapie genetika mortalita patologie MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- Kaplanův-Meierův odhad MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- multicentrické studie jako téma MeSH
- nádorové biomarkery analýza genetika MeSH
- prognóza MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-bcl-2 analýza genetika MeSH
- randomizované kontrolované studie jako téma MeSH
- registrace statistika a číselné údaje MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: The PRIMA study (ClinicalTrials.gov identifier: NCT00140582) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS: Patients (> 18 years of age) with previously untreated high-tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS: In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION: Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.
- MeSH
- časové faktory MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- folikulární lymfom farmakoterapie mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- pozorné vyčkávání * MeSH
- progrese nemoci MeSH
- protinádorové látky imunologicky aktivní aplikace a dávkování škodlivé účinky MeSH
- rituximab aplikace a dávkování škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m2 on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.
- MeSH
- bendamustin hydrochlorid aplikace a dávkování MeSH
- cyklofosfamid aplikace a dávkování škodlivé účinky MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- doxorubicin aplikace a dávkování škodlivé účinky MeSH
- folikulární lymfom farmakoterapie MeSH
- humanizované monoklonální protilátky aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- prednison aplikace a dávkování škodlivé účinky MeSH
- protinádorové látky imunologicky aktivní škodlivé účinky terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- rituximab aplikace a dávkování škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vinkristin aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
In follicular lymphoma (FL), no prognostic index has been built based solely on a cohort of patients treated with initial immunochemotherapy. There is currently a need to define parsimonious clinical models for trial stratification and to add on biomolecular factors. Here, we confirmed the validity of both the follicular lymphoma international prognostic index (FLIPI) and the FLIPI2 in the large prospective PRIMA trial cohort of 1135 patients treated with initial R-chemotherapy ± R maintenance. Furthermore, we developed a new prognostic tool comprising only 2 simple parameters (bone marrow involvement and β2-microglobulin [β2m]) to predict progression-free survival (PFS). The final simplified score, called the PRIMA-PI (PRIMA-prognostic index), comprised 3 risk categories: high (β2m > 3 mg/L), low (β2m ≤ 3 mg/L without bone marrow involvement), and intermediate (β2m ≤ 3 mg/L with bone marrow involvement). Five-year PFS rates were 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively (P < .0001). In addition, achieving event-free survival (EFS) or not at 24 months (EFS24) was a strong posttreatment prognostic parameter for subsequent overall survival, and the PRIMA-PI was correlated with EFS24. The results were confirmed in a pooled external validation cohort of 479 patients from the FL2000 LYSA trial and the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. Five-year EFS in the validation cohort was 77%, 57%, and 44% in the PRIMA-PI low-, intermediate-, and high-risk groups, respectively (P < .0001). The PRIMA-PI is a novel and easy-to-compute prognostic index for patients initially treated with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores.
- MeSH
- beta-2-mikroglobulin metabolismus MeSH
- folikulární lymfom * metabolismus mortalita patologie terapie MeSH
- imunoterapie * MeSH
- kostní dřeň metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- nádorové proteiny metabolismus MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma. METHODS: We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS: Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).
- MeSH
- antitumorózní látky aplikace a dávkování škodlivé účinky MeSH
- dospělí MeSH
- folikulární lymfom farmakoterapie mortalita MeSH
- humanizované monoklonální protilátky aplikace a dávkování škodlivé účinky MeSH
- imunologické faktory aplikace a dávkování škodlivé účinky MeSH
- indukční chemoterapie MeSH
- Kaplanův-Meierův odhad MeSH
- leukopenie chemicky indukované MeSH
- lidé středního věku MeSH
- lidé MeSH
- nauzea chemicky indukované MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- rituximab aplikace a dávkování škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
BACKGROUND: Dulanermin-a non-polyhistidine-tagged soluble recombinant human apoptosis ligand 2 (Apo2L) or tumour-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-has pro-apoptotic activity in a range of cancers and synergistic preclinical activity with rituximab against lymphoma in vivo. We aimed to assess the safety, pharmacokinetics, and efficacy of dulanermin and rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma. METHODS: We did an open-label phase 1b/2 randomised study. Four study centres in the USA enrolled patients into phase 1b, and 27 study centres in the USA, Italy, Australia, France, Czech Republic, New Zealand, and Poland enrolled patients into phase 2. In phase 1b, patients (age ≥18 years) with indolent B-cell non-Hodgkin lymphoma with stable disease or better lasting at least 6 months after the most recent rituximab-containing regimen were included. In phase 2, patients (age ≥18 years) with follicular lymphoma grades 1-3a were included. In phase 1b, patients received 4 mg/kg or 8 mg/kg intravenous dulanermin on days 1-5 of up to four 21-day cycles and intravenous rituximab 375 mg/m(2) weekly for up to eight doses. In phase 2, patients were randomly assigned (1:1:1) centrally by an interactive voice response system to dulanermin (8 mg/kg for a maximum of four 21-day cycles), rituximab (375 mg/m(2) weekly for up to eight doses), or both in combination, stratified by baseline follicular lymphoma International Prognostic Index (0-3 vs 4-5) and geographic site (USA vs non-USA). The primary endpoints of the phase 1b study were the safety, tolerability, and pharmacokinetics of dulanermin with rituximab. The primary endpoint of phase 2 was the proportion of patients who achieved an objective response. All patients who received any dose of study drug were included in safety analyses. Efficacy analyses were per protocol. Treatment was open label; all patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, NCT00400764. FINDINGS: Between June 6, 2006, and Feb 15, 2007, 12 patients were enrolled in phase 1b, and between April 4, 2007, and April 20, 2009, 60 patients were enrolled in phase 2, of whom 59 were included in safety analyses and 58 in efficacy analyses. No dose-limiting toxic effects were noted in phase 1b. The most common grade 1-2 adverse events in phase 1b were fatigue (nine; 75%), rash (five; 42%), and chills, decreased appetite, diarrhoea, and nausea (four each; 33%). 19 grade 3 or higher adverse effects were noted in five (42%) patients, with 14 occurring in one patient. After treatment with 8 mg/kg of dulanermin, in six patients the mean serum peak concentration was 80 μg/mL, dropping below the minimum detectable concentration (2 ng/mL) within 24 h after the dose. The mean steady state peak and trough concentrations of rituximab were 461 μg/mL (SD 97.5) and 303 μg/mL (92.8), respectively. In phase 2, eight (14%) of 59 patients experienced 12 grade 3 or higher adverse events. In phase 2, objective responses were noted in 14 of 22 (63.6%, 95% CI 41.8-81.3) patients treated with rituximab only, 16 of 25 (64.0%, 43.1-81.5) treated with dulanermin and rituximab, and one of 11 (9.1%, 0.5-39.0) treated with dulanermin only. The study was terminated early, on May 5, 2010, because of an absence of efficacy in the combination group. INTERPRETATION: The addition of dulanermin to rituximab in patients with indolent B-cell non-Hodgkin lymphoma was tolerable but did not lead to increased objective responses. This combination is not being developed further in non-Hodgkin lymphoma. FUNDING: Genentech and Amgen.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- B-buněčný lymfom farmakoterapie MeSH
- folikulární lymfom farmakoterapie MeSH
- lidé MeSH
- protein TRAIL terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- recidiva MeSH
- rituximab terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Austrálie MeSH
- Česká republika MeSH
- Francie MeSH
- Itálie MeSH
- Nový Zéland MeSH
- Polsko MeSH
- Spojené státy americké MeSH
Vascular endothelial growth factor is involved in lymphoma growth, suggesting a potential role for anti-vascular endothelial growth factor therapies in hematologic malignancies. In this phase III study, patients with CD20-positive diffuse large B-cell lymphoma were randomized to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus either placebo (R-CHOP) or bevacizumab (RA-CHOP). Treatment was administered every 21 (8 cycles) or 14 days (6 cycles plus 2 rituximab cycles) as per institutional practice. An early analysis of risk/benefit by the Data and Safety Monitoring Board showed that RA-CHOP increased cardiotoxicity without prolonging progression-free survival compared with R-CHOP, and the trial was stopped early. The study protocol was amended to allow for 12 additional months of follow up to evaluate safety. With 787 patients enrolled, median follow up was 23.7 and 23.6 months for R-CHOP and RA-CHOP, respectively. Median progression-free survival for R-CHOP and RA CHOP was 42.9 and 40.2 months, respectively (hazard ratio=1.09; P=0.49). The proportion of deaths was identical for R-CHOP (83 of 387, 21%) and RA-CHOP (82 of 390, 21%). Relative to R-CHOP, RA-CHOP had a higher rate of left ventricular ejection fraction perturbation (18% vs. 8%; odds ratio=2.51; 95% confidence interval (CI): 1.60-3.93) and congestive heart failure (16% vs. 7%; odds ratio=2.79; 95%CI: 1.72-4.54). Bevacizumab added to R-CHOP increased cardiac events, without increasing efficacy, arguing against further evaluation of RA-CHOP in patients with diffuse large B-cell lymphoma. The MAIN study is registered at clinicaltrials.gov identifier:00486759.
- MeSH
- cyklofosfamid aplikace a dávkování MeSH
- difúzní velkobuněčný B-lymfom diagnóza farmakoterapie MeSH
- dospělí MeSH
- doxorubicin aplikace a dávkování MeSH
- humanizované monoklonální protilátky aplikace a dávkování MeSH
- inhibitory angiogeneze aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myší monoklonální protilátky aplikace a dávkování MeSH
- prednison aplikace a dávkování MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vinkristin aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
- MeSH
- analýza přežití MeSH
- azacytidin * aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- myelodysplastické syndromy * farmakoterapie MeSH
- riziko MeSH
- senioři MeSH
- statistika jako téma MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
