Management of cutaneous T cell lymphoma: new and emerging targets and treatment options

Cutaneous T cell lymphomas (CTCL) clinically and biologically represent a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the most common subtypes. Over the last decade, new immunological and molecular pathways have been identified that not only influence CTCL phenotype and growth, but also provide targets for therapies and prognostication. This review will focus on recent advances in the development of therapeutic agents, including bortezomib, the histone deacetylase inhibitors (vorinostat and romidepsin), and pralatrexate in CTCL

Nivolumab combined with brentuximab vedotin for R/R primary mediastinal large B-cell lymphoma: A 3-year follow-up

Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) have poor responses to salvage therapy. Nivolumab and brentuximab vedotin (BV) showed promising early efficacy in patients with R/R PMBL in the phase 1/2 open-label, multicenter CheckMate 436 study; we report safety and efficacy findings from the 3-year follow-up. Patients who were eligible were aged ≥15 years with R/R PMBL previously treated with either high-dose chemotherapy plus autologous hematopoietic cell transplantation (HCT) or ≥2 prior multiagent chemotherapies, and had Eastern Cooperative Oncology Group performance status scores of 0 to 1 and CD30 expression of ≥1%. Patients were treated with nivolumab 240 mg and BV 1.8 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points included complete response rate, duration of response, progression-free survival (PFS), and overall survival (OS). Safety was monitored throughout. At final database lock (30 March 2022), 29 patients had received nivolumab plus BV; median follow-up was 39.6 months. Investigator-assessed ORR was 73.3%; median time to response was 1.3 months (range, 1.1-4.8). Median PFS was 26.0 months; median OS was not reached. PFS and OS rates at 24 months were 55.5% (95% confidence interval [CI], 32.0-73.8) and 75.5% (95% CI, 55.4-87.5), respectively. The most frequently occurring grade 3/4 treatment-related adverse event was neutropenia. Consolidative HCT was received by 12 patients, with a 100-day complete response rate of 100.0%. This 3-year follow-up showed long-term efficacy for nivolumab plus BV in R/R PMBL, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT02581631

Positron-emission tomography–based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Results: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. Conclusion: In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy

The outcome of peripheral t-cell lymphoma patients failing first-line therapy: A report from the prospective, international t-cell project

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation. (Registered at clinicaltrials.gov identifier: 01142674)

Developing limits for driving under cannabis

ABSTRACT Objective Development of a rational and enforceable basis for controlling the impact of cannabis use on traffic safety. Methods An international working group of experts on issues related to drug use and traffic safety evaluated evidence from experimental and epidemiological research and discussed potential approaches to developing per se limits for cannabis. Results In analogy to alcohol, finite (non-zero) per se limits for delta-9-tetrahydrocannabinol (THC) in blood appear to be the most effective approach to separating drivers who are impaired by cannabis use from those who are no longer under the influence. Limited epidemiological studies indicate that serum concentrations of THC below 10 ng/ml are not associated with an elevated accident risk. A comparison of meta-analyses of experimental studies on the impairment of driving-relevant skills by alcohol or cannabis suggests that a THC concentration in the serum of 7-10 ng/ml is correlated with an impairment comparable to that caused by a blood alcohol concentration (BAC) of 0.05%. Thus, a suitable numerical limit for THC in serum may fall in that range. Conclusions This analysis offers an empirical basis for a per se limit for THC that allows identification of drivers impaired by cannabis. The limited epidemiological data render this limit preliminary

Integrating acute stroke telemedicine consultations into specialists' usual practice: a qualitative analysis comparing the experience of Australia and the United Kingdom

Stroke telemedicine can reduce healthcare inequities by increasing access to specialists. Successful telemedicine networks require specialists adapting clinical practice to provide remote consultations. Variation in experiences of specialists between different countries is unknown. To support future implementation, we compared perceptions of Australian and United Kingdom specialists providing remote acute stroke consultations. Specialist participants were identified using purposive sampling from two new services: Australia's Victorian Stroke Telemedicine Program (n = 6; 2010-13) and the United Kingdom's Cumbria and Lancashire telestroke network (n = 5; 2010-2012). Semi-structured interviews were conducted pre- and post-implementation, recorded and transcribed verbatim. Deductive thematic and content analysis (NVivo) was undertaken by two independent coders using Normalisation Process Theory to explore integration of telemedicine into practice. Agreement between coders was M = 91%, SD = 9 and weighted average κ = 0.70. Cross-cultural similarities and differences were found. In both countries, specialists described old and new consulting practices, the purpose and value of telemedicine systems, and concerns regarding confidence in the assessment and diagnostic skills of unknown colleagues requesting telemedicine support. Australian specialists discussed how remote consultations impacted on usual roles and suggested future improvements, while United Kingdom specialists discussed system governance, policy and procedures. Australian and United Kingdom specialists reported telemedicine required changes in work practice and development of new skills. Both groups described potential for improvements in stroke telemedicine systems with Australian specialists more focused on role change and the United Kingdom on system governance issues. Future research should examine if cross-cultural variation reflects different models of care and extends to other networks

Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly

Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis

Not available

Controversies in the treatment of lymphoma with autologous transplantation

High-dose therapy and autologous stem cell transplant (HDT-ASCT) is the standard of care for relapsed and refractory diffuse large B cell lymphoma and Hodgkin's lymphoma; however, the role for HDT-ASCT in the treatment of follicular lymphoma (FL), mantle cell lymphoma (MCL), and peripheral T cell lymphoma (PTCL) is controversial. In FL, phase II and randomized data support the use of HDT-ASCT in the relapsed setting and incorporation of rituximab into mobilization regimens and post-transplant maintenance appears to prolong remission durations. Allogeneic stem cell transplant remains the only curative treatment option and is appropriate for patients with high bone marrow disease burdens and refractory disease. In MCL, HDT-ASCT is most often administered up front, and phase II studies using intense immunochemotherapy followed by HDT-ASCT in first complete response (CR) have shown the most impressive outcomes. Complicating the situation, however, are data supporting up-front intensive immunochemotherapy without HDT-ASCT consolidation as well as a "watch and wait" strategy for selected patients. Finally, in PTCL, phase II data support treatment with HDT-ASCT in first CR, and it is rarely appropriate in the relapsed setting. Furthermore, disease status at the time of transplant likely impacts outcome; however, this needs to be evaluated further. Overall, HDT-ASCT is an important element of the treatment of relapsed FL and untreated MCL and PTCL; however, large prospective studies are needed to confirm its role and identify the most optimal induction, mobilization, and maintenance regimens for each disease