How to define intermediate stage in Hodgkin's lymphoma?

Abstract:  Background : Intermediate or unfavourable stage Hodgkin's lymphoma (HL) definition relies upon at least three different scoring systems defined by cooperative groups (EORTC, GHSG and Canadian-ECOG). We aimed to investigate their efficacy and their correlation with International Prognostic Score (IPS) for advanced HL. Patients and methods : We studied a population of 1156 patients with localized stage HL treated prospectively within GELA centres in H8 (518 patients) and H9 (638 patients) protocols. Median age: 30 yr, 18%, Female 50%; stage I: 25%; stage II: 75%. According to scoring systems 70% had 0–1 EORTC factors; 60% 0–1 GHSG factors and 82% 0–1 Canadian factors. The IPS for advanced stages was available only in H9 study with 64% 0–1 factor. Results : Survival curves according to each of the different scoring systems could significantly discriminate the subgroup populations. When a multivariate Cox analysis was performed for overall survival (OS) including all the scoring system variables: age >45 yr, sex male, Haemoglobin <10.5 g/dL, lymphocytes <600/ μ L, B symptoms with elevated ESR, extra nodal sites did retain an independent significant value. Probability of OS was 99%, 98%, 92%, 82% and 73% for patients with 1–5 factors, respectively P  < 0.0001. Conclusion : These factors are similar for most of them with those described in the IPS when stages III and IV are replaced by extra nodal localization. This new score should be validated in other prospective trials, as it will simplify the Hodgkin prognostic scoring systems for localized and advanced stages.     

Hodgkin's lymphoma

Hodgkin's lymphoma was first described in 1832, but the nature of the pathognomic Reed-Sternberg cell, on which diagnosis of the disease is based, has only been elucidated in the past few years. Radiotherapy has been used to treat localised disease since the 1940s, and in the 1960s, effective combination chemotherapy regimens were introduced for anatomically advanced disease. The past three decades have witnessed continued improvement in outcome to such an extent that Hodgkin's lymphoma is now one of the most curable of all non-cutaneous malignancies. With improved survival and extended follow-up, relevance of treatment-induced late effects has become apparent, and modern therapeutic strategies must fully account for these effects. We review the pathology of Hodgkin's lymphoma, and its clinical presentation, investigation, present management, and natural history, including late effects of treatment.     

Hodgkin's lymphoma in adults

Management of Hodgkin's lymphoma continues to develop. Outcomes for patients with favourable-risk, early-stage disease are excellent, and serial reductions in intensity of treatment have been made to retain the excellent prognosis while reducing the late effects of treatment. Prognosis is also very good in advanced-stage disease but the rate of relapse is higher than in early-stage disease, and the optimum first-line treatment is unclear. Workers are investigating the role of functional imaging to assess whether treatment can be tailored according to response, with the most intensive therapies reserved for patients predicted to have poor outcomes. In this Seminar we critically appraise the management of Hodgkin's lymphoma in early-stage disease, advanced-stage disease, and at relapse, with a focus on late effects of treatment.     

Prognostic factors in advanced stage Hodgkin's lymphoma: the significance of the number of involved anatomic sites

BACKGROUND: Advanced Hodgkin's lymphoma (HL) is curable by conventional chemotherapy in 60--70% of patients. The pretreatment identification of a sizeable subgroup of patients with sufficiently low failure-free survival (FFS) to be eligible for investigational treatment is necessary. OBJECTIVES: To determine the prognostic significance of the number of involved sites (NIS) in patients with advanced HL and its relationship to the International Prognostic Score (IPS). METHODS: A retrospective review of patients with advanced HL, defined as Ann Arbor stage (AAS) IB, IIB, III or IV, treated with anthracycline-based regimens. The end-point was FFS. RESULTS: We identified 277 patients with a median age of 32 yr (14--78), 57% of whom were males. AAS was I in 4% of patients, II in 29%, III in 38% and IV in 29%. B-symptoms were recorded in 81%. Most patients had nodular sclerosis (64%) and mixed cellularity (26%) histology. IPS was greater-than-or-equals 3 in 44% of 242 evaluable patients. The NIS was greater-than-or-equals 5 in 32% of the patients and 20% of all patients had both greater-than-or-equals 5 involved sites and IPS greater-than-or-equals 3. The 10-yr FFS was 67%, being 76% vs. 50% for patients with less-than-or-equals 4 vs. greater-than-or-equals 5 involved sites (P < 0.0001). The NIS (greater-than-or-equal 5), AAS IV and anemia were independent predictors of FFS in multivariate analysis. The NIS remained significant along with IPS, when the latter was included in the analysis. Patients with greater-than-or-equals 5 involved sites and IPS greater-than-or-equals 3 had 10-yr FFS overall, and relapse-free survival of 41%, 45% and 49%, respectively. CONCLUSIONS: The NIS was associated with FFS in advanced HL, was independent of IPS, and led to the identification of a sizeable subgroup of patients with 10-yr FFS of approximately 40%. This factor should be evaluated during the development of prognostic systems.     

霍奇金淋巴瘤的治疗进展

自1832年Thomas Hodgkin发表"淋巴结和脾脏的一些病态外观"[1]以来,对霍奇金淋巴瘤(HL)的研究已超过1个世纪。最初,这种疾病被认为无法救治,随着化学治疗(化疗)和放射治疗(放疗)方案的逐步完善,初发早期HL的5年生存率已高达90%以上。剖腹探查术曾用于对疾病的分     

Advances in the treatment of Hodgkin's lymphoma

Given the successful treatment for most patients with Hodgkin's lymphoma, efforts have been directed primarily toward improving outcomes for the minority of patients with poor prognosis or relapsed disease or reducing the late effects of therapy for long-term survivors. Recently, a simple and clinically useful prognostic scoring system was developed for patients with advanced disease. This system allows better risk assessment for individual patients and more uniformity among patients participating in clinical trials. In addition, trials using newer chemotherapeutic regimens such as Stanford V or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) are maturing with promising results. Other studies are helping to define the role of high-dose therapy for patients with Hodgkin's lymphoma, although biologic treatments such as cellular or antibody-based therapies are still in early phases of development. Lastly, positron emission tomographic scanning is emerging as a useful tool in staging and following Hodgkin's lymphoma.     

Pathogenesis of Hodgkin's lymphoma

Abstract:  In Hodgkin's lymphoma (HL), the B cell origin of the tumour cells, the Hodgkin and Reed-Sternberg (HRS) cells, has been disclosed by molecular single cell analysis about 10 yr ago. This finding formed the basis for various studies aimed to better understand the pathogenesis of this peculiar malignancy and the pathophysiology of the HRS cells. Work of our groups in this regard was focussed recently on two main topics, namely the study of differential gene expression in HRS cells and the pathogenesis of composite lymphomas. Composite lymphomas are combinations of HL and B cell non-Hodgkin lymphomas, that turned out to be often clonally related. By molecular analysis of several composite lymphomas for potential transforming events, we identified examples of both shared as well as distinct transforming events. Comparing gene expression profiles of HL-derived cell lines with the corresponding profiles from other B cell lymphomas and normal B cell subsets revealed a global down-regulation of the B cell-specific gene expression signature in HRS cells. Moreover, we identifed aberrant expression and activity of multiple receptor tyrosine kinases in HRS cells of classical and to a lesser extend lymphocyte predominant HL, which appears to be a unique feature of HL, and may offer novel strategies for treatment.     

Immunotherapy of Hodgkin's lymphoma

Abstract:  Many new treatment approaches have given promising results in experimental Hodgkin's lymphoma (HL) models. Early clinical trials evaluating antibody based compounds as immunotoxins (ITs), radioimmunotherapy (RIT), bispecific molecules (BSMs), and recently monoclonal antibodies (MAbs), have demonstrated some clinical efficacy in patients with advanced refractory or relapsed HL. In addition, cellular immunotherapy is evolving. Although it seems unlikely to cure chemotherapy resistant patients with larger tumor masses by either of these approaches alone, the combination with conventional chemotherapy might help to overcome resistance of Hodgkin-/Reed-Sternberg (H-RS) cells. Another rationale for the development of these immunotherapies is to eliminate residual disease and thereby to prevent relapses from the disease. Currently, several clinical studies are running. A murine MAb (Ki-4) based 131 Iodine conjugate has shown efficacy in refractory HL patients in a phase II study, but less toxic constructs using alternate MAbs or isotopes should be developed. A humanized as well as a fully human anti-CD30 MAb are being tested in clinical phase I/II studies. These MAbs could engage the human immune system against the H-RS cells. In addition, these MAbs could be then combined with conventional chemotherapy in order to improve the treatment of HL.     

Checkpoint inhibitors in Hodgkin's lymphoma

Hodgkin's lymphoma is unusual among cancers in that it consists of a small number of malignant Hodgkin/Reed–Sternberg cells in a sea of immune system cells, including T cells. Most of these T cells are reversibly inactivated in different ways and their reactivation may induce a very strong immune response to cancer cells. One way of reactivation of T cells is with antibodies blocking the CTLA‐4 and especially with antibodies directed against PD‐1 or the PD‐L1 ligand thereby reversing the tumor‐induced downregulation of T‐cell function and augmenting antitumor immune activity at the priming (CTLA‐4) or tissue effector (PD‐1) phase. Immune checkpoint inhibitors have been evidenced as an additional treatment option with substantial effectiveness and acceptable toxicity in heavily pretreated patients with Hodgkin's lymphoma. Particularly, PD‐1 blockade with nivolumab and pembrolizumab has demonstrated significant single‐agent activity in this select population.     

Pembrolizumab in classical Hodgkin's lymphoma

Pembrolizumab is a humanized monoclonal antibody directed against programmed cell death protein 1 (PD‐1), a key immune‐inhibitory molecule expressed on T cells and implicated in CD4+ T‐cell exhaustion and tumor immune‐escape mechanisms. Classical Hodgkin's lymphoma (cHL) is a unique B‐cell malignancy in the sense that malignant Reed–Sternberg (RS) cells represent a small percentage of cells within an extensive immune cell infiltrate. PD‐1 ligands are upregulated on RS cells as a consequence of both chromosome 9p24.1 amplification and Epstein–Barr virus infection and by interacting with PD‐1 promote an immune‐suppressive effect. By augmenting antitumor immune response, pembrolizumab and nivolumab, another monoclonal antibody against PD‐1, have shown significant activity in patients with relapsed/refractory cHL as well as an acceptable toxicity profile with immune‐related adverse events that are generally manageable. In this review, we explore the rationale for targeting PD‐1 in cHL, review the clinical trial results supporting the use of checkpoint inhibitors in this disease, and present future directions for investigation in which this approach may be used.     

Importance of determination of serum beta-2-microglobulin levels in patients with Hodgkin's lymphoma

The authors evaluated retrospectively in a group of 69 adult patients with Hodgkin's lymphoma the relationship between the beta-2-microglobulin serum level, basic demographic parameters (age, sex) and factors characterizing the extent (stage III and IV, "bulk" or mediastinal mass, number of affected areas of lymph nodes) and activity of the tumour (presence of B-symptoms, red cell sedimentation rate, haemoglobin, albumin and lactate dehydrogenase level, number of leucocytes and lymphocytes). They analyzed also the possible prognostic impact of beta-2-microglobulin on the therapeutic response risk of relapse and patient's survival. Methods of univariant statistical analysis confirmed the correlation of beta-2-microglobulin level with all investigated metric parameters of patients (advanced age, number of affected nodes, red cell sedimentation rate and lactate dehydrogenase level, lower albumin, haemoglobin level, numbers of leucocytes and lymphocytes). In multivariant analysis however the only independent metric markers significantly associated with an elevated protein level were more advanced age of the patients (P = 0.0002) and a lower number of leucocytes (P = 0.05). The values of beta-2-microglobulin was not influenced by the extent of the tumour (stage III and IV, "bulk" or mediastinal mass, higher number of affected areas of lymph nodes). Significantly more frequently elevated protein values were recorded in patients with manifestations of B symptoms associated with the diagnosis (P = 0.0003). Multivariant analysis did not prove the importance of the serum level of beta-2-microglobulin as a prognostic factor in the sense of predicted remission, development of a relapse or death in conjunction with progression of Hodgkin's lymphoma.     

Immunotherapies for Hodgkin's lymphoma

Multiple immune evasion strategies characterize the pathobiology of Hodgkin's lymphoma. These must be considered when developing and testing immunotherapeutic approaches for this disease. The clinical experience with adoptive immunotherapy of Epstein-Barr virus positive tumors, and with monoclonal antibodies directed against CD30, CD20, and other antigens, is herein reviewed.     

Epstein-Barr virus-associated Hodgkin's lymphoma

Survivors of Hodgkin's lymphoma (HL) frequently have many years to experience the long-term toxicities of combined modality therapies. Also, a significant proportion of HL patients will relapse or have refractory disease, and less than half of these patients will respond to current salvage strategies. 30-50% of HL cases are Epstein-Barr virus associated (EBV-positive HL). The virus is localized to the malignant cells and is clonal. EBV-positive HL is more frequent in childhood, in older adults (>45 years) and in mixed cellularity cases. The survival of EBV-positive HL in the elderly and the immunosuppressed is particularly poor. Despite improvements in our understanding of EBV-positive HL, the true contribution of EBV to the pathogenesis of HL remains unknown. Increased knowledge of the virus' role in the basic biology of HL may generate novel therapeutic strategies for EBV-positive HL and the presence of EBV-latent antigens in the malignant HL cells may represent a target for cellular immunotherapy.