SummaryBackground Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the effi cacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.

Recent advances in the treatment of multiple myeloma (MM) have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the work-up of MM, and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease (MRD) is important for prognosis and treatment planning, and has underscored an unmet need for sensitive imaging modalities that accurately assess response to therapy in MM. Low dose whole body computed tomography (WBCT) has increased sensitivity compared to conventional skeletal survey (CSS) in the detection of bone disease, and can reveal information leading to changes in therapy and management that could prevent or delay the onset of significant morbidity and mortality related to skeletal-related events. Given the multiple options for detection of bone and bone marrow lesions ranging from CSS to WBCT, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI), the International Myeloma Working Group has established guidelines on the optimal and standardized use of imaging modalities in different stages of the disease. These recommendations on imaging within and outside of clinical trials will help to standardize the imaging worldwide in order to allow comparison of results and unification of treatment approaches.

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Immunoglobulin is a highly diverse autologous molecule able to influence immunity in different physiological and diseased situations. Its effect may be visible both in terms of development and function of B and T lymphocytes. Polyclonal immunoglobulin may be used as therapy in many diseases in different circumstances such as primary and secondary hypogammaglobulinemia, recurrent infections, polyneuropathies, cancer, after allogeneic transplantation in the presence of infections and/or GVHD. However, recent studies have broadened the possible uses of polyclonal immunoglobulin showing that it can stimulate certain sub-populations of T cells with effects on T cell proliferation, survival and function in situations of lymphopenia. These results present a novel and considerable impact of intravenous immunoglobulin (IVIg) treatment in situations of severe lymphopenia, a situation that can occur in cancer patients after chemo and radiotherapy treatments. In this review paper the established and experimental role of polyclonal immunoglobulin will be presented and discussed as well as the manufacturing processes involved in their production.

T cell diversity was once thought to depend on the interaction of T cell precursors with thymic epithelial cells. Recent evidence suggests, however, that diversity might arise through the interaction of developing T cells with other cells, the identity of which is not known. In this study we show that T cell diversity is driven by B cells and Ig. The TCR Vβ diversity of thymocytes in mice that lack B cells and Ig is reduced to 6 × 102 from wild-type values of 1.1 × 108; in mice with oligoclonal B cells, the TCR Vβ diversity of thymocytes is 0.01% that in wild-type mice. Adoptive transfer of diverse B cells or administration of polyclonal Ig increases thymocyte diversity in mice that lack B cells 8- and 7-fold, respectively, whereas adoptive transfer of monoclonal B cells or monoclonal Ig does not. These findings reveal a heretofore unrecognized and vital function of B cells and Ig for generation of T cell diversity and suggest a potential approach to immune reconstitution.

Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.

The ability to mount an immune defense against infectious microorganisms and their products, and against tumors is believed to be a direct function of lymphocyte diversity. Because the diversity of lymphocyte receptor genes is >1000-fold more diverse than the entire genome and varies between genetically identical individuals, measuring lymphocyte diversity has been a daunting challenge. We developed a novel technique for measuring lymphocyte diversity directly using gene chips. We reasoned and here demonstrate that the frequency of hybridization of nucleic acids coding for lymphocyte receptors to the oligonucleotides on a gene chip varies in direct proportion to diversity. We applied the technique to detect changes in lymphocyte diversity in mice with known B cell alterations and in persons with known T cell repertoire defects. This approach is the first to provide direct analysis of lymphocyte receptor diversity and should facilitate fundamental study of the adaptive immune system and clinical efforts to assess immunological diseases. In addition, this approach could be more broadly applied, for example to measure diversity of viral quasi-species.

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.