Measuring response to chemotherapy is a backbone of the clinical management of patients with acute leukemia. This task has historically relied on the ability to identify leukemic cells among normal bone marrow cells by their morphology. However, more accurate ways to identify leukemic cells have been developed, which allow their detection even when they are present in small numbers that would be impossible to be recognized by microscopic inspection. The levels of such minimal residual disease (MRD) are now widely used as parameters for risk assignment in acute lymphoblastic leukemia (ALL) and increasingly so in acute myeloid leukemia (AML). However, different MRD monitoring methods may produce discrepant results. Moreover, results of morphologic examination may be in stark contradiction to MRD measurements, thus creating confusion and complicating treatment decisions. This review focusses on the relation between results of different approaches to measure response to treatment and define relapse in childhood acute leukemia.
Acute lymphoblastic leukemia; Acute myeloid leukemia; Flow cytometry; Polymerase chain reaction; Minimal residual disease; Remission
Castleman and Towne described a disease presenting as a mediastinal mass resembling thymoma. It is also known as "giant lymph node hyperplasia", "lymph node hamartoma", "angiofollicular mediastinal lymph node hyperplasia", and "angiomatous lymphoid hyperplasia". The pathogenesis is unknown, but the bulk of evidence points toward faulty immune regulation, resulting in excessive B-lymphocyte and plasma-cell proliferation in lymphatic tissue. In addition to the mediastinal presentation, extrathoracic involvement in the neck, axilla, mesentery, pelvis, pancreas, adrenal gland, and retroperitoneum also have been described. There are 2 major pathologic variations of Castleman disease: (1) hyaline-vascular variant, the most frequent, characterized by small hyaline-vascular follicles and capillary proliferation; and (2) the plasma-cell variant, in which large lymphoid follicles are separated by sheets of plasma cells. The hyaline-vascular cases usually are largely asymptomatic, whereas the less common plasma-cell variant may present with fever, anemia, weight loss, and night sweats, along with polyclonal hypergamma-globulinemia. Castleman disease is a rare lymphoproliferative disorders. Few cases have been described world widely. In this article we reviewed the classification, pathogenesis, pathology, radiological features and up to date treatment with special emphasis on the role of viral stimulation, recent therapeutic modalities and the HIV-associated disease.
Castleman disease; Hyaline vascular variant; Plasma cell variant; Unicentric; Multicentric Castleman disease; Human immunodeficiency virus
Malignant lymphoma encompasses a wide variety of distinct disease entities. It is generally more common in developed countries and less common in developing countries. The East Asia region has one of the lowest incidence rates of malignant lymphoma. The incidence of malignant lymphoma around the world has been increasing at a rate of 3-4% over the last 4 decades, while some stabilization has been observed in developed countries in recent years. The reasons behind this lymphoma epidemic are poorly understood, although improving diagnostic accuracy, the recent AIDS epidemic, an aging world population and the increasing adoption of cancer-causing behaviors are suggested as contributing factors. Etiologies of malignant lymphoma include infectious agents, immunodeficiency, autoimmune disease, exposure to certain organic chemicals, and pharmaceuticals. The distribution of many subtypes exhibit marked geographic variations. Compared to the West, T/natural killer (NK) cell lymphomas (T/NK-cell lymphoma) and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are relatively more common, whereas other B-cell lymphomas, particularly follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, are less common in Asia. Some subtypes of T/NK-cell lymphomas defined by Epstein-Barr virus association are predominantly Asian diseases, if not exclusively so. Both ethnic and environmental factors play roles in such diversity. In this review, we discuss the geographic distribution and etiology of malignant lymphoma, as well as the trend.
Malignant lymphoma; Epidemiology; Asia
Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic tool to treat multiple myeloma (MM). DC-based idiotype vaccination was recently suggested to induce idiotype-specific immune responses in MM patients. However, the clinical results so far have been largely disappointing, and the clinical effectiveness of such vaccinations in MM still needs to be demonstrated. DC-based therapies against MM may need to be boosted with other sources of tumor-associated antigens, and potent DCs should be recruited to increase the effectiveness of treatment. DCs with both high migratory capacity and high cytokine production are very important for effective DC-based cancer vaccination in order to induce high numbers of Th1-type CD4+ T cells and CD8+ cytotoxic T lymphocytes. The tumor microenvironment is also important in the regulation of tumor cell growth, proliferation, and the development of therapeutic resistance after treatment. In this review, we discuss how the efficacy of DC vaccination in MM can be improved. In addition, novel treatment strategies that target not only myeloma cells but also the tumor microenvironment are urgently needed to improve treatment outcomes.
Cellular immunotherapy; Dendritic cell; Multiple myeloma; Cytotoxic T lymphocyte; Immune response
Hodgkin lymphoma (HL) represents one of the great success stories in hematology going from a uniformly fatal disease, to one that is curable in the vast majority of cases. Despite this success, some patients experience relapse. To address this unmet need a variety of agents, classes of drugs, and strategies have demonstrated activity in HL recurring after autologous hematopoietic stem cell transplantation. These include chemotherapeutics (gemcitabine-based combinations, bendamustine), histone deacetylase (HDAC) inhibitors (panobinostat), immunomodulatory agents (lenalidomide), mTOR inhiobitors (everolimus), monoclonal antibodies (rituximab), and antibody-drug conjugates (brentuximab vedotin) as well the potential of long-term disease control via allogeneic transplantation. Such advances reflect our increased understanding of the biology of HL and hold promise for continued improved outcomes for those suffering with this condition.
Hodgkin lymphoma; Antibody drug conjugates; allogeneic transplant; HDAC inhibitor; IMID; mTOR
Natural Killer (NK) cells are the third population of lymphocyte in the mononuclear cell compartment that triggers first-line of defense against viral infection and tumor transformation. Historically, NK cells were thought of as components of innate immunity based on their intrinsic ability to spontaneously kill target cells independent of HLA antigen restriction. However, it is now clear that NK cells are quite sophisticated and use a highly specific and complex target cell recognition receptor system arbitrated via a multitude of inhibitory and activating receptors. Killer cell immunoglobulin-like receptors (KIR) are the key receptors of human NK cells development and function. To date, fourteen distinct KIRs have been identified: eight are inhibitory types, and six are activating types. The number and type of KIR genes present varies substantially between individuals. Inhibitory KIRs recognize distinct motifs of polymorphic HLA class I molecules. Upon engagement of their specific HLA class I ligands, inhibitory KIR dampen NK cell reactivity. In contrast, activating KIRs are believed to stimulate NK cell reactivity when they sense their ligands (unknown). KIR and HLA gene families map to different human chromosomes (19 and 6, respectively), and their independent segregation produces a wide diversity in the number and type of inherited KIR-HLA combinations, likely contributing to overall immune competency. Consistent with this hypothesis, certain combinations of KIR-HLA variants have been correlated with susceptibility to diseases as diverse as autoimmunity, viral infections, and cancer. This review summarizes our emerging understanding of KIR-HLA diversity in human health and disease.
NK cells; Innate immunity; HLA; KIR; Polymorphism; Immune genes
Multiple myeloma is a malignancy of B-cells that is characterized by the clonal expansion and accumulation of malignant plasma cells in the bone marrow. This disease remains incurable, and a median survival of 3-5 years has been reported with the use of current treatments. Viral-based therapies offer promising alternatives or possible integration with current therapeutic regimens. Among several gene therapy vectors and oncolytic agents, adenovirus has emerged as a promising agent, and it is already being used for the treatment of solid tumors in humans. The main concern with the clinical use of this vector has been its high immunogenicity; adenovirus is often able to induce a strong immune response in the host. Furthermore, new limitations in the efficacy of this therapy, intrinsic to the nature of tumor cells, have been recently observed. For example, our group showed a strong antiviral phenotype in vitro and in vivo in a subset of tumors, shedding new insights that may explain the partial failure of clinical trials based on this promising new therapy. In this review, we describe novel therapeutic approaches that implement viral-based treatments in hematological malignancies and address the novelty as well as the possible limitations of these new therapies, especially in the context of the use of adenoviral vectors for treating multiple myeloma.
Adenovirus; Oncolytic therapy; Multiple myeloma; Antiviral phenotype
Chronic GVHD was recognized as a complication of allogeneic hematopoietic cell transplantation more than 30 years ago, but progress has been slowed by the limited insight into the pathogenesis of the disease and the mechanisms that lead to development of immunological tolerance. Only 6 randomized phase III treatment studies have been reported. Results of retrospective studies and prospective phase II clinical trials suggested overall benefit from treatment with mycophenolate mofetil or thalidomide, but these results were not substantiated by phase III studies of initial systemic treatment for chronic GVHD. A comprehensive review of published reports showed numerous deficiencies in studies of secondary treatment for chronic GVHD. Fewer than 10% of reports documented an effort to minimize patient selection bias, used a consistent treatment regimen, or tested a formal statistical hypothesis that was based on a contemporaneous or historical benchmark. In order to enable valid comparison of the results from different studies, eligibility criteria, definitions of individual organ and overall response, and time of assessment should be standardized. Improved treatments are more likely to emerge if reviewers and journal editors hold authors to higher standards in evaluating manuscripts for publication.
Chronic graft-versus-host disease; Treatment; Phase II clinical trials; Review
On April 23, 1951, a 30-year-old woman received the first intentional ABOi (ABO incompatible) renal transplantation in Boston. At that time, it was commonly believed that intensely rinsing the graft to remove blood would be sufficient to overcome any immunological problems associated with blood type incompatibility. However, when the abovementioned patient and another ABOi transplant recipient died within a month, Humes and colleagues arrived at the same conclusion: "We do not feel that renal transplantation in the presence of blood incompatibility is wise." In the decades that followed, we learned that the oligosaccharide surface antigens representing the ABO-blood group antigens are expressed not only on erythrocytes but also on cells from various tissues, including the vascular endothelium. The growing gap between organ demand and availability has sparked efforts to overcome the ABO barrier. After its disappointing results in the early 1970s, Japan became the leader of this endeavor in the 1980s. All protocols are based on 2 strategies: removal of preformed antibodies with extracorporeal techniques and inhibition of ongoing antibody production. Successful ABOi renal transplantation became possible with the advent of splenectomy, new immunosuppressive drugs (e.g., rituximab, a monoclonal antibody against CD20), and extracorporeal methods such as antigen-specific immunoadsorption. This review summarizes the underlying pathophysiology of ABOi transplantation and the different protocols available. Further, we briefly touch potential short- and long-term problems, particularly the incidence of infectious complications and malignancies, that can arise with high-intensity immunosuppressive therapy.
Graft survival; Graft loss; Rejection; Preconditioning
Through the phase 3 International Randomized Study of Interferon vs. STI571 (IRIS) trial, imatinib emerged as the standard treatment for chronic myeloid leukemia (CML) and has successfully prolonged the duration of both the chronic phase (CP) and the disease-free state. The majority of newly diagnosed patients treated for CP-CML achieve a complete cytogenetic response (CCyR), and over time, most of these eventually achieve major molecular responses (MMRs) and even complete molecular responses (CMRs). In ongoing phase 3 randomized trials of second-generation tyrosine kinase inhibitors (TKIs), nilotinib and dasatinib have been found to have superior efficacies in helping achieve cytogenetic and molecular responses, including MMRs and CMRs. However, only the MMR rate was significantly higher in bosutinib compared with the imatinib control, but not in CCyR rate. Current reports of imatinib discontinuation suggested that achieving CMR is an important prerequisite for CML to be cured. Recent data from the STIM (Stop Imatinib) trial showed that imatinib can be successfully discontinued in patients who achieve a certain level of CMR. Standardized real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) assays have been available in routine clinical practice, and efforts are being focused on achieving higher sensitivity and optimizing the time of imatinib discontinuation. Although very few patients are cured by administration of only Bcr-Abl TKIs, including imatinib and second-generation TKIs, current advances may eventually make this possible. This report summarizes the detailed clinical data obtained in the DASISION, ENESTnd, and BELA studies and discusses high-sensitivity detection methods and future therapeutic strategies.
CML; Imatinib; Nilotinib; Dasatinib; PCR; Leukemia stem cell
Graft-versus-host disease (GVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT) and this occurs as donor T lymphocytes, activated by recipient antigen presenting cells (APC), attack the host tissues or organs. This APC activation is a crucial initial step of influencing the outcome of GVHD and is mediated by innate immune signaling. Toll-like receptors (TLRs) and nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are important components of innate immunity; both families of receptors are known for sensing various microbial ligands or danger signals. Signaling through TLRs/NLRs regulate activities of APCs, through phagocytosis, cytokine and chemokine release, delivery of APCs from peripheral tissues to draining lymph nodes, and antigen presentation. Several TLRs/NLRs have been identified and their ligands and signaling pathways have been described. Recent findings suggest a significant association of TLR/NLR polymorphisms with the increased risk for severe GVHD. Therefore, these TLR/NLR pathways likely contributing to immune response for GVHD may serve as novel therapeutic targets to facilitate allograft tolerance. This review summarizes the role of TLRs/NLRs innate immune receptors and signaling in GVHD pathophysiology.
Innate immunity; GVHD; Transplantation; TLR; NLR
Chronic graft-versus-host disease (CGVHD) is one of the most significant complications of long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). CGVHD may have protean manifestations and can pose unique diagnostic and therapeutic challenges. New recommendations that emphasize the importance of qualitative differences, as opposed to time of onset after HSCT, are now being used to standardize the diagnosis and clinical assessment of CGVHD, but they require validation. During the past 3 decades, experimental studies and clinical observations have elucidated the mechanisms of acute GVHD, but its biology is much less well-understood. Experimental studies have generated at least 4 theories to explain the pathophysiology of CGVHD: (1) thymic damage and the defective negative selection of T cells, (2) regulatory T cell deficiencies, (3) auto-antibody production by aberrant B cells, and (4) the formation of profibrotic lesions. Mouse models have provided important insights into the pathophysiology of CGVHD, and these have helped improve clinical outcomes following allo-HSCT, but no animal model fully replicates all of the features of CGVHD in humans. In this article, recent clinical changes, the pathogenesis of CGHVD, the cellular and cytokine networks implicated in its pathogenesis, and the animal models used to devise strategies to prevent and treat CGVHD are reviewed.
Chronic graft-versus-host disease; Pathophysiology; Acute graft-versus-host disease; Fibrosis; Mouse model
Despite significant recent advances in the applicability and outcome following unrelated cord blood transplantation (UCBT), infections remain a major cause of mortality associated with poor immune recovery in the first 6 months after UCBT. Enhanced immune reconstitution not only could improve survival by reduced transplant related mortality, but may also favorably impact on relapse incidence by improved graft-versus-leukemia effects. This review will summarize our current understanding of the biology of immune recovery post-UCBT with an emphasis on adaptive T cell dependent immunity. New efforts to boost immunity will be also highlighted including our own laboratory, where ex vivo T cell expansion is pursued towards adoptive immunotherapy.
Cord blood stem cell transplantation; Opportunistic infection; Immune reconstitution; Adoptive immunotherapy; Graft vs leukemia effect