Hodgkin lymphoma (HL) remains one of the most curable human cancers, as modern combination chemotherapy and radiation therapy cure ∼80% of patients. Over the last two decades, the major efforts were ...focused on the development of more intensive front-line regimens for patients with advanced stage HL, decreasing the number of chemotherapy cycles and radiation therapy field and doses for patients with early-stage HL and incorporating positron emission tomography imaging in diagnostic, prognostic, and treatment planning. More recently, the improved knowledge of the molecular biology of the disease led to the development of highly active new agents, including the antibody–drug conjugate brentuximab vedotin and immune checkpoint inhibitors. Accordingly, the current efforts are focusing on incorporating these new agents into standard of care regimens, aiming at further improving cure rates, while reducing treatment-related toxicity. In this review, we will focus on the current status of HL therapy and how the development of new agents is re-shaping standard of care regimens.
The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately ...60% of patients. Many clinical trials have been carried out over the last 10years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed.
Reports of phase III trials evaluating the addition of molecularly targeted agents or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phases I and II trials which preceded these phase III trials were also reviewed.
Among six phase III trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary end point. The other five trials did not show an improved outcome with the addition of the new agent. The preceding phases I and II trials were very heterogeneous in their end points and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase III trials.
The standard of care for DLBCL is still R-CHOP. Phase I/II trials failed to predict the results of subsequent phase III trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase II trials evaluating new agents in DLBCL needs to be better defined in the future.
•Recently published phase II trials of anti PD1/PD-L1 combination regimens are heterogeneous.•Other immunotherapeutic agents and targeted agents are the more common partners.•Trials design is mainly ...non-randomized, while ORR represents the most used primary endpoint.•Across the different studies, ORRs span from 0 to 91% and G ≥ 3 TEAEs go from 0 to 100%.•Only a minority of these combinations proceed to phase III and eventually receive approval.
A high number of combinations of PD-1/PD-L1 inhibitors with other anti-cancer therapies are in clinical development. The usefulness of phase II trials in evaluating their efficacy and safety is unclear.
We performed a systematic search on PubMed and Cochrane Library for phase II trials of PD-1/PD-L1 inhibitors in combination with other anti-cancer therapies (systemic therapy and/or radiotherapy) published between January 1st 2018 and December 31st 2020. Study design, primary endpoint and main outcomes were registered for each paper.
119 articles reporting on 65 regimens were included in our analysis. Backbone agents were more frequently PD-1 inhibitors (pembrolizumab = 47, nivolumab = 41, camrelizumab = 3) followed by anti-PD-L1 (durvalumab = 19, atezolizumab = 6, avelumab = 3). Therapeutic partners were other immunotherapeutic agents (n = 46), targeted therapies (n = 40), chemotherapy (n = 22) or radiotherapy (n = 11). The majority of articles reported on single-arm trials (n = 87, 73%) and response rate was the most frequent primary endpoint (n = 69, 58%). Objective responses, registered in 109 (92%) articles, ranged between 0% and 91%. The incidence of grade 3 or higher treatment-related adverse events, clearly reported in 97 (82%) articles, spanned from 0 to 100%. Five combinations received regulatory approval by Food and Drug Administration or European Medicine Agency for 9 different indications, based on the results of a phase II trial (n = 3) or on a confirmatory phase III trial (n = 6).
The landscape of phase II trials evaluating PD-1/PD-L1 inhibitors with other anticancer therapies is heterogeneous. Combinations of two immunotherapeutic agents have been the most investigated. Only a minority of indications (8%) granted regulatory approval.
Histologic transformation in marginal zone lymphomas Conconi, A.; Franceschetti, S.; Aprile von Hohenstaufen, K. ...
Annals of oncology,
November 2015, 2015-Nov, 2015-11-00, 20151101, Letnik:
26, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of ...MZL patients.
The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs mucosa-associated lymphoid tissue (MALT) lymphoma, 46%, 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).
With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases 3.8%, 95% confidence interval (95% CI) 2%–6.5%. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3–9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%–20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%–86%).
In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.
In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative ...Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.
•Recent experience with targeted anticancer drugs and immunotherapies suggest the traditional approach of using the maximal tolerated dose (MTD) is not ideal.•Project Optimus recommends optimizing the dosage of oncology drugs to ensure they are both effective and tolerable.•MDICT developed practical recommendations for the design and conduct of phase I oncology trials.
We performed a systematic review of phase I trials specifically designed for lymphoma patients. PubMed and Cochrane Library databases were searched using (lymphoma*) AND (phase 1) and publication ...date 2015–2020 to identify phase I dose-finding trials including a majority of lymphoma patients. Eighty-two trials (n = 3289 lymphoma patients) were included: 46 (55%) enrolled only lymphoma patients, 34 (41%) included also other hematologic malignancies, 2 (2%) solid tumors. Forty-six trials (56%) evaluated a combination (in 25 addition of experimental drug to standard therapy). Seven trials (9%) enrolled untreated patients. Among trials reporting activity in lymphoma patients, 74% (n = 57) reported an overall response rate ≥ 30%. All trials reported grade ≥ 3 adverse events; however, rates were not comparable across trials. Thirty-one treatment-related deaths in lymphoma patients were reported (overall treatment-related grade 5 adverse events rate 0.94%). Phase I trials designed for lymphoma patients were generally safe and the majority reported overall response rate ≥ 30%.
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•Phase I trials represent the first clinical evaluation of a new drug or combination.•Several phase I trials have been designed specifically for lymphoma patients.•We identified 82 trials (2015–2020) including a majority of lymphoma patients.•These trials were overall safe, the majority reported an overall response rate≥ 30%.•A greater degree of standardization in reporting safety results should be encouraged.
Background: Treatment aimed at eradicating Helicobacter pylori infection results in lymphoma remission in most localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas. The aim of this ...survey is to investigate the long-term effect of this therapeutic approach in a large series of patients. Methods: One hundred and five patients with localized gastric MALT lymphoma were initially treated only with H. pylori eradication regimens. Lymphoma responses were graded using the Wotherspoon score. Results: Helicobacter pylori, detected by histology in 81% of cases, was eradicated in all positive patients. Histological regression of the lymphoma was achieved in 78 of 102 assessable patients 76%, 95% confidence interval (CI): 67% to 84% with complete remission (score 0–2) in 66 and partial remission (score 3) in 12. At a median follow-up time of 6.3 years, histological remission was consistently confirmed in 33 of 74 assessable patients, while 25 had score fluctuations (from 0 to 4) and 13 presented a lymphoma relapse (score 5). Only one patient had a distant progression. Transformation to a large-cell lymphoma was seen in two cases. The 5- and 10-year overall survival is 92% (95% CI: 84% to 96%) and 83% (95% CI: 70% to 91%), respectively. Only one patient died of lymphoma after transformation to a high-grade lymphoma. Conclusions: Helicobacter pylori eradication resulted in complete lymphoma remission in the majority of cases. Long-term clinical disease control was achieved in most patients. A watch and wait policy appears to be safe in patients with minimal residual disease or histological-only local relapse.
Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important ...therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models.
Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed.
Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib.
The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.
Despite improvements in the diagnosis and management of lymphomas, many patients remain incurable with available treatments. advances in preclinical research and a better understanding of the ...molecular biology of lymphomas have allowed the development of a high number of therapeutic agents with innovative mechanisms of action. Many of these new agents have shown activity in patients not responding to standard treatments and there is optimism that their incorporation into the standard of care can result in improved treatment outcomes. Here we review new monoclonal antibodies and small molecules that have recently entered clinical evaluation for patients with lymphomas.
•Ball bearings suffer when working in harsh environmental conditions.•Impact of contaminant’s size, hardness, and concentration level on bearings’ rating life.•New light on the procedure of wear ...progress on bearings’ life.•Experimental study of bearings’ deterioration.
Ball bearings’ rating life is reduced when they are installed, operated and maintained under harsh environmental conditions as they suffer from excessive wear due to debris contaminants in the lubricant. This life reduction is taken into account when calculating the modified rating life but the impact of contaminant’s variables such as size, hardness and concentration level are not determined in detail. In this work, greases contaminated with particles of different sizes and hardness (steel and corundum) are tested to shed new light in the way these parameters and wear’s progress are related. A test rig is utilized and the most recent methods on vibration analysis regarding bearings’ condition and estimated residual life are assessed and evaluated. At the end of the tests, optical inspections using a stereoscope verify the vibration analyses results. It can be concluded that wear is more severe when harder particles are used, but regarding their size, it seems that wear progresses in a different manner depending on particle’s hardness and brittleness as soft ductile particles are rolled over and hard brittle particles are crushed down.
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