Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that arises in a proportion of individuals who are long-term carriers of human T-lymphotropic virus type 1. The median ...survival of aggressive subtypes is 8 to 10 months; with chemotherapy-based approaches, overall survival has remained largely unchanged in the ∼35 years since ATL was first described. Through the use of 4 representative case studies, we highlight advances in the biological understanding of ATL and the use of novel therapies such as mogamulizumab, as well as how they are best applied to different subtypes of ATL. We discuss the implementation of molecular methods that may guide diagnosis or treatment, although we accept that these are not universally available. In particular, we acknowledge discrepancies in treatment between different countries, reflecting current drug licensing and the difficulties in making treatment decisions in a rare disease, with limited high-quality clinical trial data.
Display omitted
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematologic malignancy linked to HTLV-1 infection, which is refractory to therapy. The precise mechanism of oncogenesis in ATLL is incompletely ...understood, however, oncogenic viral genes Tax and Hbz are implicated, and recent large genomic and transcriptome studies provide further insight. Despite progress in understanding the disease, survival and outcome with current therapies remain poor. Long-term survivors are reported, primarily among those with indolent disease or activating CC chemokine receptor 4 mutations, however, allogeneic hematopoietic stem cell transplant is the only curative treatment option. The majority of patients succumb to their disease and ongoing and collaborative research efforts are needed. I will review recent updates in HTLV-1-associated ATLL epidemiology, pathogenesis, therapy, and prevention.
Mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell ...leukemia/lymphoma (ATL). This phase II study evaluated efficacy and safety of mogamulizumab in ATL patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the US, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n=47) or investigator's choice of chemotherapy (n=24). The primary end point was confirmed overall response rate (cORR) confirmed on a subsequent assessment at 8 weeks by blinded independent review. ORR was 11% (95%CI: 4-23%) and 0% (95%CI: 0-14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95%CI: 0.41-1.21) and, after
adjustment for performance status imbalance, 0.57 (95%CI: 0.337-0.983). The most frequent treatment-related adverse (grade ≥3) events with mogamulizumab were infusion-related reaction and thrombocytopenia (each 9%). Relapsed/refractory ATL is an aggressive, poor prognosis disease with a high unmet need. Investigator's choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile.
Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD) are common and potentially fatal complications after allogeneic transplantation with mismatched donors ...and T-cell depletion. Haplo-cord transplantation combines a mismatched UCB graft with third-party cells. Conditioning involves thymoglobulin. EBV reactivation and PTLD were common in initial patients. As of March 2017, we administered a prophylactic dose of rituximab 375 mg/m
2
pre-transplant. Among 147 patients who did not receive rituximab, the cumulative incidence of post-transplant EBV reactivation and of EBV PTLD was 13% and 8%, respectively. Among 51 who received pre-transplant rituximab, the incidences were 2% (p = .0017) and 0% (p = .04), respectively. There was no difference in time to hematopoietic recovery, in the incidence of CMV reactivation, of invasive blood stream infections or of proven or probable invasive fungal infections. Pre-transplant administration of rituximab is an effective and nontoxic intervention that drastically reduces EBV reactivation and PTLD in high-risk patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose of Review
ATL is a rare and highly aggressive T cell malignancy caused by HTLV-1. We will review the state of the art of ATL epidemiology, pathogenesis, diagnosis, and treatment.
Recent ...Findings
Because of population migration, cases of ATL in non-HTLV-1 endemic countries including North America and Europe are increasingly recognized. ATL has diverse clinical manifestations, limited treatment options not widely available globally, and poor prognosis despite therapy. A small subset of patients may achieve prolonged survival with antiviral therapy or allogeneic stem cell transplant. Mogamulizumab, an anti-CCR4 monoclonal antibody, and lenalidomide, an immunomodulatory drug, are approved for ATL in Japan. Molecular studies have identified key alterations in T cell signaling and DNA methylation that may further guide drug development. Patients should be encouraged to enroll in prospective clinical trials when possible.
Summary
Ongoing, collaborative, international research continues to elucidate disease pathogenesis and contribute to an evolving therapeutic landscape for ATL.
Abstract Objective To assess the effectiveness of a tailored theory-based, Web-delivered intervention (Young Adults Eating and Active for Health) developed using community-based participatory ...research process. Design A 15-month (10-week intensive intervention with a 12-month follow-up) randomized, controlled trial delivered via Internet and e-mail. Setting Thirteen college campuses. Participants A total of 1,639 college students. Intervention Twenty-one mini-educational lessons and e-mail messages (called nudges) developed with the non-diet approach and focusing on eating behavior, physical activity, stress management, and healthy weight management. Nudges were short, frequent, entertaining, and stage-tailored to each behavior, and reinforced lesson content. Main Outcome Measure All participants were assessed at baseline, postintervention (3 months from baseline), and follow-up (15 months from baseline) for primary outcomes of weight, body mass index (BMI), fruit and vegetable intake (FVI), physical activity (PA), and perceived stress; and secondary outcomes of waist circumference, percent dietary fat, energy from sugar-sweetened beverages, servings of whole grains, self-instruction and regulation for mealtime behavior, hours of sleep, and stage of readiness for change for consuming 5 cups of FVI, completing 150 minutes of PA/wk, and managing stress on most days of the week. Demographics were collected at baseline. Analysis Chi-square analysis and mixed-models repeated measures analysis were performed to determine differences between experimental and control outcomes. Results There were no differences between experimental and control participants in BMI, weight, and waist circumference. There were small improvements in FVI ( P = .001), vigorous PA in females ( P = .05), fat intake ( P = .002), self-instruction ( P = .001), and regulation ( P = .004) for mealtime behavior, and hours of sleep ( P = .05) at postintervention, but improvements were not maintained at follow-up. At postintervention, a greater proportion of experimental participants were in the action/maintenance stages for FVI ( P = .019) and PA ( P = .002) than control. Conclusions and Implications Young Adults Eating and Active for Health is one of the first studies to use the community-based participatory research process of PRECEDE-PROCEED to develop a non-diet approach intervention. Although there were no differences between experimental and control participants in weight change or BMI, the intervention supported positive change in behaviors that may mediate excessive weight gain, such as increasing FVI and more healthful self-regulation mealtime behaviors immediately postintervention. Additional strategies to maintain the behavior changes need to be explored.
Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received ...approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors.
XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3.
PDF
