Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), but cytotoxic T lymphocytes (CTL) may play a critical role in controlling CMV reactivation. Fluorescent HLA-peptide tetramers containing immunodominant peptides from CMV were used to prospectively monitor the recovery of CMV CTL in recipients of allogeneic transplants from siblings (n ‫؍‬ 13) or unrelated donors (n ‫؍‬ 11). In patients given allografts from a sibling when both the patient and donor were seropositive for CMV before SCT, recovery of CMV-specific CTL was rapid and reached up to 21% of all CD8 ؉ T cells. Early reconstitution of CMV-specific immunity was not observed if either the donor or recipient was seronegative for CMV. In recipients of transplants from volunteer unrelated donors, recovery of CMV-specific CTL was delayed in comparison to that in recipients of transplants from siblings and no CTL were observed within the first 100 days after SCT. CTL numbers were increased after episodes of CMV reactivation but were suppressed by prednisolone therapy. Recovery of CMV-specific CTL to levels greater than 10 ؋ 10 6 /L was associated with protection from CMV disease. It was concluded that use of HLA-peptide tetramers to quantify CMV CTL is valuable for studying T-cell responses after allogeneic SCT. It should allow prediction of CMV reactivation in individual patients and assist in the development of adoptive T-cell immunotherapy. (Blood. 2001;97:1232-1240)

Purpose Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches. Methods Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology—Human T-Lymphotropic Virus and Related Retroviruses—in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents. Results As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement). Conclusion This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL

ScopeThis guideline is aimed at providing healthcare professionals with clear guidance on the management of patients with diffuse large B-cell lymphoma (DLBCL). Disease confined to specific extranodal sites, such as primary central nervous system lymphoma, testicular lymphoma, primary mediastinal large B-cell lymphoma, DLBCL of leg type, etc., is beyond the scope of this guideline. It is not the intention of this guideline to provide treatment recommendations for all situations and clinicians are advised to make management decisions taking into account individual patient circumstances. MethodologyThe guideline group was selected to be representative of UK experts in the assessment and treatment of DLBCL. Recommendations are based on a systematic review of published English language literature up to January 2015. MEDLINE database was searched using the key words DLBCL, treatment, radiotherapy and transplant. References from relevant publications were also searched. Other published guidelines, including the US National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology guidelines, were also noted.The writing group produced a draft guideline. Review of the manuscript was performed by the British Committee for Standards in Haematology (BCSH) by the Haemato-oncology sounding board of the British Society for Haematology (BSH). This consists of 50 or more members of the BSH who have reviewed this Guidance and commented on its content and applicability in the UK setting. It has also been reviewed by a patient representative nominated by the Lymphoma Association, but the Association does not necessarily approve or endorse the contents. Recommendation gradingThe Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified on the BCSH web site. BackgroundThis is a new evidence-based guideline on behalf of the BCSH for the management of diffuse large B-cell non-Hodgkin lymphoma following a primary systematic review of the evidence by the writing group using the methodology described above.Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma (NHL), accounting for 30-40% of all cases (Rodriguez-Abreu et al, 2007). Although most patients are cured with 6-8 cycles of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy, about 10-15% have primary refractory disease and a further 20-30% relapse. The

The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5 micromol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-gamma production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3+ T cells was significantly reduced in the presence of imatinib (1-5 micromol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.

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