A randomized trial comparing the CD19-specific CAR T-cell therapy tisagenlecleucel with salvage chemotherapy followed by high-dose therapy and autologous hematopoietic stem-cell transplantation in ...patients with refractory or early relapsed aggressive B-cell lymphoma did not show a longer event-free survival with CAR T cells.
Waldenström's Macroglobulinemia (WM) is a rare type of indolent non-Hodgkin lymphoma (NHL) that remains incurable. Several effective agents such as monoclonal antibodies (in combination with ...chemotherapy), Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and BCL2 inhibitors are (becoming) available for the treatment of relapsed and refractory WM. There is however no consensus on a preferred treatment in the relapsed setting. Choice of therapy in relapsed WM should be individualized by taking several treatment and patients characteristics into account, such as treatment duration, toxicity, age, comorbidities and MYD88
L265P
and CXCR4 mutational status. Due to better understanding of WM biology and the arrival of novel anti-lymphoma agents, the therapeutic options are increasing. Non-cytotoxic and fixed duration regimens, such as those explored in other indolent NHLs should be the focus of future clinical trials in WM.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions.
We conducted an individual patient data meta-analysis ...to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer.
We identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL).
We analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer.
Exercise significantly improved UBMS (β=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (β=0.29, 95% CI 0.23 to 0.35), LBMF (β=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (β=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was >60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was >60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise.
Exercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.
Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, ...we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)
. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4
T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration
or are in clinical studies
, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials
and may influence the design and production of autologous and allogeneic cell therapies.
Confused about Confusion Spanjaart, Anne M; van der Valk, Fleur M; van Rooijen, Geeske ...
The New England journal of medicine,
01/2022, Letnik:
386, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Confusion developed in a 49-year-old woman with relapsed diffuse large B-cell lymphoma within days after she received CAR-T therapy. She had difficulty putting words together and was disoriented but ...had no focal abnormalities noted during the neurologic examination.
Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This ...randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP.
A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat.
CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio HR, 0.82; 95% CI, 0.50 to 1.36;
= .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61;
= .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55;
= .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67;
= .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections.
Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.
Aims
CD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug‐conjugate targeting the CD30 molecule. For ...reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required.
Methods and results
We conducted a three‐round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a ‘live polling’ pre‐ and post‐instruction scoring round and a web‐based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair (κ = 0.12–0.35 for CD30‐positive tumour cell percentage and κ = 0.16–0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity (κ = 0.30–0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision‐making. Using fictional cut‐off points for percentage of tumour cell positivity, agreement was still suboptimal (κ = 0.35–0.60).
Conclusions
Lack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30‐positive neoplastic cells for clinical response.
Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not ...well‐established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two‐year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m2 compared with those receiving 800–999 mg/m2 (p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m2 had poorer PFS outcomes compared with those who received ≥600 mg/m2 (p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings.
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