Advanced and Relapsed/Refractory Hodgkin Lymphoma: What Has Been Achieved During the Last 50 Years

During the last 50 years there has been great progress in understanding the biology of Hodgkin disease, which is now called Hodgkin lymphoma (HL), since it has been definitely shown to be a lymphoid neoplasm and its B-cell origin has been documented in the vast majority of cases. Progress in biology has also resulted in the identification of numerous biological prognostic factors, which may facilitate the definition of high-risk groups of patients and provide guidance for individualized therapy. Unfortunately, biological prognostic factors have not been incorporated in prognostic models applicable in everyday practice and need prospective validation. More importantly, during the last 50 years, advanced stage HL has been transformed from a rather incurable into a highly curable disease. Chemotherapy has gradually improved in terms of efficacy. MOPP was replaced by the more efficacious and less toxic ABVD regimen, but higher cure rates with BEACOPP-escalated have come at the expense of increased toxicity. Better risk stratification, probably based on early, interim positron emission tomography (PET) evaluation, may in the near future better identify those patients who really need intensified chemotherapy. Furthermore, the intensification of chemotherapy and the optimal use of PET at the end of chemotherapy have already minimized the use of radiotherapy in advanced disease, thus reducing the risk of long-term complications. Relapsed and refractory disease has also been rendered curable in almost half of the patients with the advent of effective salvage regimens, and, mainly, autologous stem cell transplantation. Furthermore, better understanding of the biology of HL has permitted the development of targeted therapy. Anti-CD30 targeting with brentuximab vedotin (BV) was the first targeted therapy to be approved for relapsed/ refractory HL, either after autologous stem cell transplantation (auto-SCF) failure or after failure of two regimens in patients who were not candidates for transplant. Hopefully, the determination of the optimal role and timing of BV treatment and the development and approval of other targeted compounds will further improve the outcome of advanced stage as well as relapsed/refractory HL. © 2013 Elsevier Inc

Prognostic factors in Hodgkin lymphoma

During the last decades, the prognosis of Hodgkin lymphoma (HL) has been improved significantly with the introduction of effective chemotherapy and the implementation of risk-adapted treatment approaches. Identification of reliable risk factors is crucial to guide treatment over the course of disease. Both clinical and biological factors have been implicated in the prognosis of HL and are often used in prognostic scores to discriminate risk groups. To prevent under- or overtreatment, patients are usually assigned to one of the three widely established risk groups for first-line treatment, based solely on clinical risk factors. To further individualize therapeutic approaches, functional imaging with positron emission tomography (PET) is becoming more widely implemented and precisely investigated within clinical trials. Biological prognostic factors have been widely evaluated but are still not a part of standard prognostication. This review will discuss the currently established factors and risk models at first diagnosis and in the setting of relapsed/refractory disease and also focus on biological factors and PET, summarizing current standards and future perspectives. © 2016 Elsevier Inc

Treatment of splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL) is a distinct lymphoma entity characterized by an indolent clinical course and prolonged survival. Treatment is not standardized, since there are no prospective randomized trials in large series of SMZL patients. Splenectomy and rituximab represent the most effective treatment strategies used so far. The addition of chemotherapy to rituximab has not further improved the outcome, although this issue requires further investigation. Rituximab monotherapy has been associated with high response rates (∼90%), with approximately half of these responses being complete, even at the molecular level. More importantly, many of these responses are long-lasting, with a reported 7-year progression-free survival (PFS) at the rate of 69%. Maintenance rituximab treatment has been associated with further improvement of the quality of response as well as longer response duration in studies derived from one group of investigators. Based on its high efficacy and the good safety profile, rituximab represent one of the best treatment options for SMZL patients. Moreover, rituximab retains its efficacy in the relapse setting in most cases. Splenectomy is a meaningful alternative to rituximab in patients with bulky splenomegaly and cytopenias, without extensive bone marrow infiltration, who are fit for surgery. However splenectomy cannot completely eradicate the disease and it is also associated with greater morbidity or even mortality compared to rituximab. The choice of one of these two treatment approaches (rituximab or splenectomy) should mainly be based on patient's characteristics and on the disease burden. Novel agents are currently testing in low grade lymphomas including a small number of SMZL patients with promising results. © 2016 Elsevier Lt

Incorporating novel agents in the treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal stem cell (SC) disorders that mainly affect the elderly population. They are characterized by ineffective hematopoiesis which results in quantitative and qualitative cellular defects and high incidence of leukemic transformation. Recent advances in MDS research have led to the development of novel agents which appears to improve remission rates and survival when compared to best supportive care. Currently azacitidine, decitabine, and lenalidomide are approved by the US FDA for the treatment of MDS, while the activity of other novel agents such as histone deacetylase inhibitors, farnesyl-transferase inhibitors, novel thrombopoietic agents, and anti-angiogenesis molecules is under evaluation. Erythropoietin-stimulating agents, iron chelating therapy and thrombopoietin receptor ligands may also improve quality of life and possibly prolong survival in MDS patients. The only treatment modality that can achieve long-term survival is the allogeneic SC transplantation which is given only in selected patients. Moreover the heterogeneity of MDS and the patient's advanced age and co-morbidity are significant factors besides cytogenetics, IPSS and WPSS that should be taken into account during the decision-making process. Therefore clinicians should treat patients with MDS on an individual basis aiming the increase of the response rates and the decrease of treatment-associated toxicities. This can only be achieved through the better understanding of the MDS subgroups. If we can better define MDS subgroups we will be able to identify patients who will benefit from the incorporation of the novel agents, as monotherapy or in combinations regimens along with supportive care. © 2009 Elsevier Ltd. All rights reserved

Current and emerging treatment approaches for splenic marginal zone lymphoma

Introduction: Splenic marginal zone lymphoma (SMZL) represents a distinct entity within the spectrum of marginal zone lymphomas (MZL). Due to its rarity, treatment is not standardized. Areas covered: Currently two therapeutic options have been associated with the best outcome: splenectomy and rituximab. Splenectomy is associated with high response rates (~90%) with a median PFS>5 years. However, responses are not complete and it is associated with increased surgical risk as well as increased risk of septic episodes. Rituximab has shown significant efficacy with minimal toxicity in SMZL. The ORR is > 90%, with half of these responses being complete with a long duration of response. For the small proportion of SMZL with more aggressive clinical behavior, not responding or relapsing shortly after rituximab, novel agents are required. Several new drugs have shown significant activity in other low grade lymphomas. However, there is currently no trial testing the role of these agents specifically in SMZL. Expert opinion: Rituximab monotherapy currently represents the best choice for first line treatment for SMZL. Randomized studies are required in order to improve the outcome, especially for the small proportion of cases with the more aggressive clinical behavior. © 2016 Informa UK Limited, trading as Taylor & Francis Group

New insights in the mobilization of hematopoietic stem cells in lymphoma and multiple myeloma patients

Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC "niche" and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies. Copyright © 2014 Maria K. Angelopoulou et al

Nodal marginal zone lymphoma

Nodal marginal zone lymphoma (NMZL) is one of the three well-recognized entities within the broad category of marginal zone lymphoma, representing approximately 10% of the cases in this group. Patients typically present with nodal disease, usually at advanced stages, and a thorough work-up and staging are necessary in order to exclude occult extranodal involvement. NMZL shares many similarities with splenic marginal zone (SMZL) and mucosa-associated lymphoid tissue (MALT) lymphomas, such as cytology, immunophenotype, genetic abnormalities and maybe even a common cell of origin: a post-germinal memory B-cell. NMZL is characterized by an indolent course, but its prognosis is generally considered less favorable than that of SMZL and MALT lymphoma, with reported 5-year overall survival rates ranging between 55% and 89%. Therapeutic recommendations for NMZL are derived from small retrospective series or studies on larger cohorts of indolent lymphomas, which include a limited number of patients with NMZL. For localized disease, radiotherapy appears to be the treatment of choice, while rituximab-containing therapy is recommended for advanced stage disease. Due to the rarity of NMZL it is very difficult to perform prospective trials, and an international collaborative effort is necessary in order to better understand the biological features and provide evidence-based treatment recommendations. © 2014 Informa UK, Ltd

Role of FDG-PET/CT in staging and first-line treatment of Hodgkin and aggressive B-cell lymphomas

Positron emission tomography with integrated computed tomography (PET/CT) is increasingly used for the initial staging, final or even interim (mid-treatment) response assessment in malignant lymphomas. Extensive clinical experience has been gained with Hodgkin lymphoma (HL) and aggressive B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBCL) and other subtypes, which are the subject of the present review. The use of PET/CT is now considered mandatory for baseline staging in these entities, providing more accurate information and obviating the need of bone marrow biopsy (BMB) at least in HL. PET/CT has been the long-standing “gold standard” for final response assessment. Furthermore, early interim PET evaluation provides valuable prognostic information in HL and DLBCL. In HL, it appears that treatment intensification with Bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP)-escalated can improve disease control in patients with persistent PET positivity after two cycles of ABVD. However, there is no randomized evidence of survival benefit as yet. In contrast, regimens effective in overcoming the adverse impact of persistent PET positivity have not been yet described in DLBCL. The 2014 recommendations suggest the use of PET/CT for baseline staging and final response assessment in all [18F]fluorodeoxyglucose (FDG)-avid lymphoma subtypes, including the above named ones. The use of interim evaluation is not considered fully documented yet. The exact role of PET/CT in guiding treatment decisions has to be defined by ongoing and future randomized trials and evidence-based approaches are expected to become available in the near future. © 2015, Springer-Verlag Wien