Classical Hodgkin’s Lymphoma: Pathogenesis and Future Treatment Directions

Classical Hodgkin Lymphoma is a germinal center B cell malignancy. Over the past 40 years, through greater understanding of disease pathogenesis, advancements in treatment have lead to greater than 80% long-term survival rates after standard first line therapy.1 Currently, first-line management of the disease varies, most commonly involving the use of a standard chemotherapy regime (i.e. ABVD or BEACOPP), with or without the use of additional chemotherapies or involved-field radiation therapy.2 Treatment selection is influenced by disease staging at diagnosis and the need to maintain therapeutic efficacy, whilst minimising the risk of late and potentially fatal therapy-associated side effects.2 Consequently, higher than acceptable drug-associated toxicities and patient relapse represent the future challenges of this disease. Novel therapies, targeting the aberrant signalling pathways and phenotypic features of the malignant cell pool, and its associated inflammatory infiltrate, are the future direction of disease management. Currently, combination therapies targeting the PI3K/Akt/mTOR pathway and transcription modulation have shown the greatest clinical efficacy in improving survival outcomes in previously heavily treated cHL patients, with minimal side effects. Whilst these therapies do not yet achieve the clinical efficacy of first line therapies, preliminary stage I and II trials have demonstrated a reduction in drug associated toxicities and side effects relative to existing treatments for relapse. This paper will investigate current understanding of the pathogenesis of cHL, and how this has shaped the targets of novel therapies for the disease. Copyright Royal Medical Society. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISBN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2015, 23(1):48-57. doi:10.2218/resmedica.v23i1.1250 Res Medica 2015, Volume 23, Issue 1


Introduction
Adaptive immunity consists of a population of lymphocytes, which confer highly specific and long lasting immunity against pathogenic agents. 4The immune response generated can be classified as either humoral or cell mediated, and serves to eliminate pathogens from the body. 4When the normal processes that drive the development, differentiation or activation of these lymphocytes become distorted, pathologies of the immune system may result.
Approximately 95% of all lymphomas are of B cell origin.This includes Hodgkin lymphoma (HL), which accounts for 0.6% of newly diagnosed cancer cases each year and is attributed to 0.5% of all deaths due to cancer. 3,5,6The disease is associated with characteristic B symptoms, which include night sweats, fever (>38°C), and weight loss (>10%) over a 6 month period. 7The disease represents 11% of all B cell malignancies, and is considered relatively curable, owing to recent advancements in antitumour combination chemotherapies and involvedfield radiation therapy (IFRT). 6,8 can be further subdivided into classical (cHL) or nodular lymphocyte predominant.The former is characterised by the presence of mono-(Hodgkin) or multinucleated (Reed-Sternberg) neoplastic cells termed Hodgkin Reed-Sternberg (HRS) cells.9 With a bimodal age distribution of occurrence, the pathogenic mechanisms leading to development of cHL are thought to include both environmental and genetic factors, with a strong association with Epstein Barr virus (EBV) co-infection and human leukocyte antigen (HLA) genotypes I and III.9,10 Tumour composition and progression is remarkably consistent between individual cases of cHL, a factor that has contributed to the success of current therapies.11,12 Whilst these therapies have shown great clinical efficacy, higher than acceptable drug-associated toxicities and patient relapses represent the current clinical challenges of the disease.In recent years, fluorine-18 fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) has been used to tailor first and second line therapies for cHL patients.18 F-FDG-PET has shown considerable potential in improving clinical outcomes, sparing low-risk patients from overly aggressive treatments and accurately identifying high-risk patients whom may benefit from changes to standard therapy.13 Further research is, however, required to better define what constitutes a positive or negative scan, elucidate the factors which influence tracer uptake, and determine the optimal timing for when such scans should be performed.13 Increased risk of secondary neoplasms, cardiovascular and pulmonary disease, are other clinical challenges faced in the management of long-term survivors of cHL. 7Whilst advancements in radiotherapy, which have led to a reduction in the number of cycles and intensity of combination chemotherapies required, have been linked to a slight decline in risk of secondary malignancies, death from non-HL disease is still greater in this cohort relative to the general population.7,14 Following from this, the advent of new therapies and ongoing clinical trials has further emphasised the need for long-term follow up in cHL patients, to assess drug efficacy and late developing side effects.Finally, poor prognosis and death due to non-HL disease is a current challenge faced by older cHL patients.7 Relative to their younger counterparts, older cHL patients have been associated with an increased number of comorbidities and an inability to tolerate intensive treatment regimes, making delivery of first line therapies difficult.7 Future treatment strategies must look towards addressing the issues surrounding current therapy intensity and side effects to improve outcomes for patients.This review investigates how our current understanding of the pathogenesis of cHL is shaping the targets for future therapies, which aim to combat the clinical challenges raised by current disease management.Current therapy targets and efficacy will be considered in contrasts to novel therapies, their modality, side effects and expected efficacy.

Methods
Information for this paper was collected using the PubMed and UpToDate databases.Papers were selected based on relevance, using a combination of the search terms; Hodgkin lymphoma, classical Hodgkin lymphoma, pathogenesis, treatment and current therapies.Any therapies found by this search, were then searched for directly using the drug name.Data with respect to non-Hodgkin lymphoma was excluded.Articles referencing data specific to classical Hodgkin lymphoma was included.A total of 42 papers were collected for use, from June 2014 to June 2015, with papers selected post 2009 for novel therapies and post 1995 for those regarding pathogenesis of cHL.

Pathogenesis of Classical Hodgkin Lymphoma
B cell lymphomas are characterised by their phenotypic resemblance to features of normal B cells during development.In the case of cHL, HRS cells are thought to be derived from a pool of preapoptotic germinal center B cells, which have lost the capacity to express B cell receptor. 6For a given case of cHL, studies of the HRS cell population indicate identical immunoglobulin (Ig) gene rearrangement and somatic hypermutation, implicating the clonal expansion of a malignant cell population of mature, post germinal center origin. 9et upon a non-malignant, inflammatory background of lymphocyte infiltrate, HRS cells exhibit distinct features including a lack of B cell receptor and positivity for phenotypic markers such as TARC, CD15, Pax-5, MUM-1, CD138 and CD30. 15he lymphocyte infiltrate and expression of these specific surface receptors promotes the survival of this neoplastic cell population through paracrine signalling and immune suppression of anti-tumour responses.
The disease is also characterised by its links with environmental and genetic factors.Associated with one-third of all diagnosed cases of cHL in the developed world, EBV gene expression is thought to promote B cell survival, transformation and reprogramming towards a HRS cell phenotype. 9ollowing primary infection, EBV becomes latent in the host memory B cell population, such that it can persist for the lifetime of the cell.EBV encoded EBNA-1 and LMP-1 gene products are thought to be essential for the transformation of memory B cells. 9 These gene products act on intracellular signalling pathways, where EBNA-1 acts directly to down regulate tumour-suppressor gene expression, as well as supporting tumour development through up-regulation of CCL22, which promotes T regulatory cell activation. 5Similarly, LMP-1 gene product mimics the signal conferred by CD40, which acts downstream to activate NF-κB, p38, PI3K, AP1, and JAK-STAT signalling to promote cell survival. 16,17Genetic studies have also shown that crippling mutations in Ig genes, which encode the B cell receptor, are almost exclusively associated with EBV positive cases of cHL.This link is thought to be related to the EBV encoded gene LMP-2, which appears to reprogram mature B cells towards a HRS cell phenotype, promoting the rescue of germinal center B cells, lacking a B cell receptor, from apoptosis. 9e bimodal age distribution observed in cHL is supported by the delayed exposure theory. 18This theory links socioeconomic status to delayed childhood exposure to common pathogens, such as EBV, which has been associated HL development in young adults. 189][20] These factors are thought to delay exposure to common childhood infections, and result in increased severity of disease upon exposure in later life. 18In the case of EBV exposure and cHL, high socioeconomic status has been linked to increased risk of developing EBV-positive cHL in adolescence (15-39 years), whereas late onset cHL (55-79 years) is typically EBV-negative and associated with lower socioeconomic status. 18strong correlation exists between EBV-associated cHL and particular HLA genotypes.10 Cytotoxic T lymphocytes (CTLs) play a crucial role in the management of EBV infections, where their response is dependent on antigen presentation by HLA's on antigen presenting cells.Association studies have identified areas within HLA class I and class III regions of the genome, in particular alleles 126 and 284 of micro-satellite markers D6S265 and D6S510 respectively, which are linked to increased susceptibility to cHL. 10 Specifically, these regions of variance have been linked to EBV positive cases of cHL, suggesting that HLA mediated antigen presentation plays a crucial role in the pathogenesis of the disease.It is thought that in susceptible individuals, the weakened CTL response enables enhanced expansion of EBV-infected cells, with elevated titres of the virus promoting B cell transformation. 9 fter transformation, survival of the HRS cell population is dependent on the dysregulation of the cell fate through an inflammatory response which modulates a family of transcription factors, nuclear factor (NF)-κB, that enable the evasion of apoptotic pathways.Under normal conditions, NF-κB is present in an inactive state in the cell cytoplasm, transiently activated under the tight control of stimulatory signals.In the HRS cell population, NF-κB becomes inappropriately activated to confer cell survival and proliferation signals.This inappropriate activation is thought to be the consequence of EBV virus LMP-1 gene expression, which confers intrinsic signals for the up regulation of NF-κB in EBV positive tumours.9 Alternatively, in EBV negative instances of cHL, over expression of cell surface receptors (CD30), acquisition of deleterious mutations (in A20) or loss of regulatory proteins (IκB), promote the sustained signalling of NF-κB.9 NF-κB activation confers a 'rescue' signal to germinal center B cells that are destined for apoptosis, due to their inability to express a B cell receptor.As this cell population persists, the cells undergo uncontrolled clonal expansion, acquiring additional mutations, which drive them towards the malignant HRS cell phenotype.The HRS cells then secrete a milieu of cytokines, which promote the accumulation of the non-malignant inflammatory infiltrate characteristic of cHL.Together, this tumorous mass forms an environment conducive to the continued survival of the HRS clone.

Diagnosis and staging of classical Hodgkin Lymphoma
The diagnosis and staging of cHL is crucial to the management and treatment of the disease.Identified by the presence of HRS cells, the disease is most commonly diagnosed via light microscopy and immunohistochemistry of tissue biopsies exhibiting lymphadenopathy, preferably through obtaining an entire lymph node from the affected region. 21Once a cHL diagnosis has been confirmed, staging tests are conducted to determine the extent of disease.Previously, bone marrow biopsy was a necessary component of staging, however recent utilisation of non-invasive whole body imaging procedures, such as computed tomography (CT) and positron emission tomography (PET) scans, allow the clinical staging of cHL with no detrimental impact on patient treatment or outcomes. 22Along with imaging, laboratory studies are also conducted to assist in the determination of the optimal course of therapy.These tests include complete blood count, absolute lymphocyte count, erythrocyte sedimentation rate, HIV serology, pregnancy test in women of childbearing age and liver, bone, and renal function biochemical tests.
Currently, clinical staging of cHL adopts the Cotswold-modified Ann Arbor classification system, which considers the number of sites involved, type of tissue involvement (nodal versus extranodal) and the distribution of disease (See Table 1). 23This staging method identifies patients as either early (Stage I and II) or advanced (Stage III and IV) stage disease.Early stage disease can be further stratified based of the presence or absence of certain prognostic features, which also influence the treatment strategy adopted. 7This stratification is termed favourable or non-favourable disease prognosis and has been defined by the German Hodgkin Study Group (GHSG) and the European Organisation for the Research and Treatment of Cancer (EORTC) (See Table 2). 7For patients with advanced stage disease, risk stratification tools can be useful to identify patients at risk of standard treatment failure and who may benefit from a modified or intensified treatment regime. 24The International Prognostic Index (IPI) is the most widely used scoring system, which predicts 5-year freedom from progression and overall survival rate. 24,25However, whilst the IPI is widely used, its lack of consideration for advancements in treatment has meant it is yet to be proven useful for the determination for initial therapy in disease.

Current treatment of Classical Hodgkin Lymphoma
As stated previously, the clinical staging and prognostic features for a given case of cHL largely influences treatment selection and management strategy for patients.Standard first line therapy for early stage favourable cHL involves 2 cycles of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) chemotherapy in combination with 20 Gy IFRT. 7Emerging evidence suggests that PET scans may be used to tailor treatment therapies and reduce treatment intensity through omission of IFRT. 13However, research in this area is ongoing, with some finding that whilst initial outcomes are similar in early PET-negative patients opting for or against IFRT, the risk of early relapse is significantly higher in those who omitted irradiation. 26onversely, early stage unfavourable cHL requires 4 cycles of ABVD chemotherapy in combination with 30 Gy IFRT. 3 For patients with advanced stage cHL, 6-8 cycles of ABVD or 6 cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone) are recommended as the first line therapy. 7Studies comparing the efficacy of combination chemotherapies, ABVD and BEACOPP, in advanced stage cHL, have identified that whilst escalated BEACOPP is associated with improved initial tumour control, it is also linked to increase rates of fatal acute toxicities and secondary leukaemia. 7,27Furthermore, BEACOPP based therapy are associated with increased risk of direct side effects of chemotherapy, infectious complications, blood product requirements, infertility and the development of secondary acute myeloid leukaemia. 7As the long-term outcomes for both treatment options are similar, therapy selection is often influenced by patient preference with regards to the balance between drug efficacy and toxicity.
After first line therapy, approximately 80% of cHL patients achieve long-term remission. 1However, within this population, drug-associated toxicities result in an increased mortality rate relative to the general population.Secondary neoplasms and cardiovascular disease represent the two major causes of non-relapse associated mortality for longterm survivors of cHL. 7These outcomes are often associated with increased combination therapies involving IFRT, which may result in long-term anergic immunological responses and T cell defects. 7Pulmonary toxicity is another major side effect of bleomycin-containing chemotherapies, with outcomes ranging from reduction in diffusion capacity, lung volume and vital capacity to pneumonitis and end-stage pulmonary fibrosis. 7tudies have demonstrated that 1-2% of bleomycin treated patients experience fatal pulmonary fibrosis. 7Psychological problems have also been associated with this cohort, owing to therapyinduced infertility and reduction in quality of life. 7r the remaining 20%, disease relapse and progression is by far the major cause of death after first line therapy. 7High-dose chemotherapy and autologous stem cell transplantation (SCT) represent the standard second-line treatment for refractory or relapsed cHL. 28Of those to receive second-line treatment, approximately 50% of relapsed patients and a minority of refractory patients will go on to achieve durable responses. 28t present, allogeneic SCT represents the only strategy with curative potential for those remaining patients, however treatment has been associated with high mortality rate, due to resultant graft versus host disease or fatal infection post transplantation. 28hilst 18 F-FDG-PET has been beneficial in identifying patients in whom allogeneic SCT is expected to have the greatest effect, overall survival (40-85%) and progression free survival (23-40%) remains low. 13,28In addition, the prognosis of patients who fail high dose chemotherapy and autologous SCT is poor. 28Therefore, novel therapies are needed to minimise current combination therapy associated toxicities and improve patient outcomes in the primary resistant and relapsed populations of cHL. 28

Future direction of therapies for classical Hodgkin Lymphoma
The future direction of cHL treatment looks towards agents that are highly specific for the neoplastic HRS cell population and their characteristic nonneoplastic inflammatory infiltrate microenvironment.Advancements in genomic sequencing have allowed for the identification of numerous aberrant signalling pathways specific to HRS cells and their microenvironment, which present potential targets for small-molecule therapies. 11These therapies aim to diminish the prosurvival signals and anti-apoptotic pathways conferred by the inflammatory infiltrate present in cHL, as well as target HRS cells by radiation-emitting immune conjugates. 12Since 1977, Brentuximab vedotin has been the only new therapy approved by the Food and Drug Administration for the treatment of cHL, illustrating the stark need for further research in this area. 11[31][32][33] Immunotherapies Brentuximab vedotin, the most successful immunotherapy to date, is an antibody-drug conjugate, targeted against the CD30+ HRS cells pathognomonic of cHL. 32Associated with minimal severe adverse side effects, Brentuximab is currently used in the treatment of relapsed or refractory cHL patients, with phase I and II clinical trials demonstrating an overall response rate of 75% and complete remission in 34% of patients. 32,34Since then, various other monoclonal antibody therapies have entered clinical trials for the treatment of cHL.Whilst CD20 is not constitutively present on HRS cells, anti-CD20 therapies such as rituximab are used to target the inflammatory constituents of the microenvironment.The rational for targeting CD20 is to eliminate cells such as tumour-supportive reactive B cells and putative HL-initiating cells, which are CD20 positive and confer pro-survival and progression signals to HRS cells. 12Phase II clinical trials have demonstrated an overall survival rate of 96-98% for newly diagnosed patients treated with rituximab in combination with ABVD chemotherapy, relative to the 94% achieved by ABVD alone. 35,36In addition, other monoclonal antibody therapies targeting the reactive inflammatory microenvironment observed in cHL have been developed.Alemtuzumab and Nivolumab are monoclonal antibodies against CD52 and PD1 respectively, which target the T cell contingent of the characteristic inflammatory infiltrate of cHL.These drugs act to either dampen the T cell response by antibody mediated lysis or alternatively enhance the anti-tumour response through improved T cell receptor signalling. 11,12omparative clinical trials for these drugs in cHL patients are limited, however, preliminary data for Nivolumab is promising, with its use in relapsed or refractory HL patients achieving a response rate of 87% and complete remission in 17% of patient. 37tibody mediated immunotherapies have shown efficacy in clinical trials, however, they are limited by their short half-life and need for repeat infusions.For this reason, interest has shifted towards adoptive immunotherapies to generate host directed, memory responses against tumour cells.Whilst weakly immunogenic, EBV latent membrane proteins, LMP1 and LMP2, have proved attractive targets for immunotherapy via EVB-specific CTLs in recent clinical studies on patients with EBV positive HL.These trials have shown that EBV-specific CTLs are generally well tolerated in patients post infusion, demonstrating biological activity and the capacity to induce complete or partial remission in patients with heavily pre-treated cHL. 38The benefit of EBVspecific CTL adoptive immunotherapies is the potential for the generation of a memory T cell pool, conferring long-lived immunity, with minimal toxicities that do not eliminate healthy tissues. 39owever, whilst high cure-rates are achievable, results are not consistent and treatment is limited by the ability to expand sufficient autologous CTLs from heavily pre-treated patients with relapsed disease. 39In addition, the ability to generate a longlived memory response has proven difficult owing to the weakly immunogenic nature of LMP1 and LMP2, and the tendency of tumour cells to modulate the expression of targeted antigen to enhance survival.
Research is currently under way investigating combination EBV-specific CTLs targeting both LMP1 and LMP2, demonstrating improved results. 39all Molecule Therapies Alternatively, to immunotherapies, further advancements and understanding into the oncogenic signalling pathways, which sustain the neoplastic cell population of cHL, have allowed for the development of new small molecule therapies.Studies have shown, the JAK/STAT, NF-κB, PI3K and MEK/ERK pathways are all constitutively active in HRS cells, conferring pro-survival, metabolism and immunity signals. 11,33Current clinical interest is focused on the PI3K/Akt/mTOR pathway, which contributes to the constitutive activation of NF-κB. 33verolimus and Temsirolimus are two analogues of rapamycin, which serve as mTOR inhibitors, and are currently undergoing clinical trials.Everolimus acts to down regulate the activation of NF-κB, inhibiting the subsequent survival signals, whilst Temsirolimus induces cell cycle arrest. 33Clinical trials in patients with relapsed cHL treated with Everolimus observed an overall response rate of 42%, which was generally well tolerated patients, with most patients going off the trial due to disease progression rather than due to drug associated toxicities. 11,33Conversely, JAK and NF-κB inhibitors have proven to be theoretically viable treatment options for relapsed cHL, however preliminary trials have shown minimal to no clinical significance as of yet. 11The encouraging overall response rate and ability to induce stable disease make mTOR inhibitors the current leading therapy in oncogenic signalling pathway treatments for those with relapsed cHL.
Another avenue currently being explored for the treatment of resistant and relapsed cHL is epigenetic therapies.Histone deacetylase (HDAC) inhibitors, such as Panobinostat, have demonstrated direct and indirect antitumour clinical activity.This group of drugs is thought to exert its effects through induction of cell-cycle arrest and apoptosis, inhibition of angiogenesis and promotion of an antitumour microenvironment and immune response. 40In vitro studies have demonstrated HDAC inhibitors modulate the activity of transcription factors to either down regulate the expression of chemokines such a TARC, disrupt PD1 and PDL1 signalling, or up regulate the expression of OX40L, TNFα and IL-17 to promote an antitumour microenvironment. 40,41Panobinostat is considered the most potent HDAC inhibitor against cHL, with the highest single agent activity due to its ability to target multiple cellular pathways. 40Recent Phase II clinical trials in relapsed cHL patients observed a reduction in tumour size of 74%, with 4% of patients achieving complete remission and 23% achieving partial remission. 40The drug is generally well tolerated, with studies reporting grade 1 to 2 side effects, including diarrhea, nausea, vomiting, fatigue and haematological effects such as thrombocytopenia, anaemia and neutropenia. 29e unselective nature of Panobinostat means it is capable of exerting its effects on a wide range of signalling pathways and effector molecules within malignant cells.For this reason, Panobinostat is also being considered as a potential therapy to improve the efficacy of other drugs in the treatment of cHL.Studies examining HDAC inhibitors in combination with other small molecule therapies have demonstrated a synergistic effect between the two types of drugs.Independently, Panobinostat and Everolimus demonstrate modest clinical activity as single agents in the treatment of refractory cHL.However, in a recent Phase I trial, the combination therapy of Panobinostat and Everolimus in relapsed classical HL generated an overall response rate of 43%, with 15% achieving complete remission. 30The improved efficacy of these therapies in combination is attributed to the ability of these drugs to target multiple sites within a common signalling pathway.However, due to the multifactorial effect of the drugs in combination, additive toxicities are a concern in the progression of this therapy option.
Finally, immunomodulation is an alternative therapeutic option for the treatment of cHL.Lenalidomide is an immunomodulatory drug, currently being investigated for its efficacy in cHL patients who have progressed past first line therapy.Whist the mechanism of action are incompletely understood, it is thought Lenalidomide causes direct induction of apoptosis and anti-angiogenesis in the neoplastic cell population, as well as activation of immune effector cells. 42Due to its multimodality, Lenalidomide is currently being investigated as a single-agent therapy for those who have failed conventional therapies. 42Clinical trials of oral daily lenalidomide have yielded clinical responses and disease stabilisation in heavily pretreated HL patients.The drug has also shown high patient tolerability, with the most common drug limiting toxicities including cytopenias, rash and hepatic toxicity. 11Lenalidomide appears to be a strong candidate for future therapies in patients with tumour resistance to conventional combination chemotherapies and offers minimal adverse effects.

Conclusion
The future direction of treatment for classical HL lies in targeted small molecule and immunotherapies, used in conjunction with existing treatment regimes, for the management of refractory and relapsed patients.Whilst novel therapies, such as Panobinostat and Everolimus combinations and Lenalidomide, have shown a relative reduction in drug-associated toxicities, their efficacy is yet to match that of existing treatments.Future research should look towards not only optimising the efficacy of novel therapies, but also consider the refinement and enhancement of existing prognostic tools and standard treatments.This will enable the customisation of cHL therapy for patients based on prognostic features, minimising overly aggressive treatments in good prognosis patients and accurately identifying poor-risk patients whom may benefit from changes to standard therapy.Future challenges will be met in achieving equivalent drug efficacy in novel therapies relative to those existing, and the refinement of existing prognostic tools to enable the individualised management of patients with cHL.

What is known already:
What this study adds/ highlights: • The pathogenesis and phenotypic markers of the classical Hodgkin lymphoma malignant cell population • Identification of the gaps existing in the treatment of classical Hodgkin lymphoma • Synthesis of current findings from ongoing clinical trials investigating novel therapies for the treatment of classical • Existing therapies; their targets, efficacy and side effects • Evaluation of which therapies appear most efficacious • Suggestion as to the future direction of treatment for classical Hodgkin lymphoma. •

Figure 1 .
Figure 1.Phase I and Phase II clinical trials using current and novel therapies in the treatment of patients with relapsed or refractory cHL.

Table 2 :
Comparison of the Prognostic Factors for the Determination of Early Stage Disease inclassical HL(7)