The pathobiology and treatment of Hodgkin lymphoma. Where do we go from Gianni Bonadonna’s lesson?


This article reviews the evolution of the diagnosis and treatment of Hodgkin lymphoma (HL) since its discovery in 1832. The morphological, phenotypic and molecular characteristics of both nodular lymphocyte-predominant HL and classical HL are revised in the light of recent molecular information and possible impact on the identification of risk groups as well as the use of targeted therapies. The seminal contribution of Gianni Bonadonna to developing new treatment strategies for both advanced and early-stage HL is highlighted.

Tumori 2017; 103(2): 101 - 113

Article Type: REVIEW



Simonetta Viviani, Valentina Tabanelli, Stefano A. Pileri

Article History


Financial support: The manuscript was supported by the grant “AIRC 5 × 1000”, No. 10007 to SAP.
Conflict of interest: None of the authors has any conflict of interest related to this article.

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The pathobiology of Hodgkin lymphoma


Hodgkin lymphoma (HL) is characterized by the presence of a rather low number of neoplastic cells, either multinucleated (Reed-Sternberg cells, RSCs) or mononucleated (Hodgkin cells and variants, HCs), which are encompassed in an overwhelmingly inflammatory milieu with variable cytological composition. RSCs measure about 60 µm in diameter and show a large rim of cytoplasm along with 2 or more huge nuclei with central, inclusion-like nucleoli, often acidophilic on hematoxylin and eosin staining. HCs differ from RSCs for the presence of a single nucleus (1, 2).

Historical annotations

The tumor was first described by Sir Thomas Hodgkin in 1832 (3) and subsequently termed “Hodgkin’s disease” by Samuel Wilks (4). The histogenesis of the process was a matter of debate for several decades, until the use of single-cell microdissection allowed to demonstrate the monoclonal B-cell nature of the neoplastic cells (5-6-7). Subsequently, the term “Hodgkin’s disease” was abandoned in favor of “Hodgkin lymphoma”, implying its inclusion among lymphoid neoplasms (8). On histological grounds, the Lukes and Butler classification became the reference in the mid-1960s by distinguishing 4 varieties of HL (lymphocyte predominant, nodular sclerosing [NS], mixed cellularity [MC], and lymphocyte depleted [LD]), mainly based on the composition of the microenvironment (9). This classification still represents the basis for the diagnosis of HL, although some refinements have been introduced in the meanwhile (1, 2, 8). At present, a major distinction is being made between nodular lymphocyte-predominant HL (NLPHL) and classical HL (CHL), each characterized by peculiar clinical, morphological, phenotypic and molecular features. CHL is further subdivided into 4 types: lymphocyte rich (LR), NS, MC, and LD (1, 2, 8). LRCHL was in the past lumped with NLPHL. However, although sharing architectural and microenvironmental features with the latter, it shows the morphological and phenotypic profile of CHL (1, 2).

Epidemiological notes

HL usually affects lymph nodes, except for NSCHL, which can develop in the thymus (1). About 95% of HL cases belong to the classical category; the remaining 5% correspond to NLPHL (1). In resource-rich countries, NLPHL more often occurs in males in the fourth decade of life. It has a rather indolent course with possible late recurrences and a pattern of spread similar to non-Hodgkin lymphomas (1). NLPHL can be concomitant with or preceded or followed by a peculiar modality of lymph node regression known as progressively transformed germinal centers (1, 10, 11). This is, however, not necessarily linked to NLPHL. CHL shows a bimodal age distribution with 2 peaks in the second and seventh decades of life. It is more common in men, except for NSCHL, which predominates in women (1). It has an ordered diffusion through the body, the process starting from a single node or group of adjacent nodes; this modality represents the rationale for the staging procedures (12).

Lymphocyte-predominant HL

This form of HL has unique morphological and phenotypic features. In 80% of cases it is characterized by the presence of nodules mostly composed of small B lymphocytes (CD20+, CD79a+, PAX5+) with some epithelioid elements (CD68+) (1, 2). Inside the nodules – which tend to expand and coalesce through time, producing a nodular and diffuse growth pattern – there are mononucleated cells measuring about 60 µm in diameter; these represent 1%-2% of the cellularity. They show a polylobated nuclear profile, dispersed chromatin, multiple small nucleoli (at times adjacent to the nuclear membrane), and a narrow rim of slightly basophilic cytoplasm. Because of this morphology they have been called “popcorn” cells, a term that is now almost completely abandoned in favor of “lymphocyte-predominant” cells (LPCs) (1, 2). RSCs are exceedingly rare and are usually detected only on serial sections. LPCs are surrounded by rosettes of T-helper lymphocytes (CD3+, CD279/PD1-1+, BCL6+, CD57+) and express a complete B-cell phenotype (CD20+, CD75+, CD79a+, PAX5+, BOB.1+, OCT-2+) as well as the leukocyte common antigen CD45 and – in most cases – epithelial membrane antigen (EMA) (1, 2). They also score positive for BCL6 and IRF4, a fact that – along with the presence of a high load of ongoing mutations of the variable region of the immunoglobulin heavy-chain genes (IGVHs) – points to their derivation from a cell still residing in the germinal center of secondary follicles (7). In 10%-20% of cases they express IgD and CD38, being negative for IgM and CD27 (13). This peculiar pattern is usually observed in young males and is associated with a more favorable course. A meshwork of follicular dendritic cells (FDCs) (CD21+, CD23+) is observed within the nodules. Importantly, LPCs lack expression of CD30 and CD15, which are characteristic of Hodgkin Reed-Sternberg cells (HRSCs) of CHL (1, 2). A few scattered and CD30+ reactive immunoblasts can be observed, which neither belong to the neoplastic clone nor display lymphocyte-predominant morphology (1, 2).

Besides this classic nodular, B-cell-rich appearance, LPHL can display some variant patterns (14): serpiginous/interconnected nodular, nodular with prominent extranodular LPCs, nodular with T-cell-rich background, diffuse (T-cell-rich B-cell lymphoma-like), and diffuse “moth-eaten” with B-cell-rich background. The latter 2 variants account for the 20% of cases in which no nodular pattern is observed and may be difficult to distinguish from T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), also due to the absence of FDCs and the similarity in terms of gene expression profile between the 2 neoplasms. The following elements can help under these circumstances: 1) the clinical presentation, which is aggressive with widespread disease and systemic symptoms in THRLBCL; 2) the presence of CD279/PD1+ T-cell rosettes around otherwise canonical LPCs; 3) the expression of PU.1 and the negativity for LSP.1 in LPCs, the opposite pattern being observed in the neoplastic elements of THRLBCL; 4) the presence of a residual nodule with the typical characteristics of NLPHL (15-16-17-18).

On molecular grounds, LPCs harbor clonally rearranged immunoglobulin genes. As mentioned above, the clonal rearrangements can be easily detected in the DNA of single microdissected neoplastic cells, and the variable region of IGVHs carries a high load of somatic mutations showing signs of ongoing mutations (9, 19). Epstein-Barr virus (EBV) infection detected by EBER 1/2 in situ hybridization may be found in LPCs in 3%-5% of cases in both children and adults (20). EBV may be also present in bystander lymphocytes. BCL6 rearrangements (involving IG, IKAROS, ABR and other partner genes) are present in about half of NLPHL cases (21). Aberrant somatic hypermutations are found in 80% of cases, most frequently in PAX5 but also in PIM1, RHOH/TTF and MYC (22). Mutations of the genes SGK1, DUSP2 and JUNB are also reported in about half of NLPHL cases by targeted next-generation sequencing (23). An increased risk of NLPHL has been noted in some families (24). NLPHL has also been identified in patients affected by Hermansky-Pudlak type 2 syndrome (25) or autoimmune lymphoproliferative syndrome with mutations in FAS (26).

As previously mentioned, NLPHL in its nodular and nodular and diffuse forms develops slowly, with frequent late relapses. It usually remains responsive to therapy and thus is rarely fatal (1, 2). Histopathological variants characterized by the presence of LPCs outside B-cell nodules or B-cell depletion of the microenvironment or THRLBCL-like transformation are associated with advanced disease and a higher relapse rate than typical NLPHL (27). Therefore, it is useful to note the mentioned variant features in the diagnostic report (28). Progression to diffuse large B-cell lymphoma (DLBCL) has been observed in approximately 3%-5% of cases (29, 30). The neoplastic cells in such cases maintain their typical immunophenotype. DLBCL associated with NLPHL, if localized, generally has a good prognosis. A clonal relationship between NLPHL and the associated DLBCL has been reported (31-32-33). Bone marrow involvement is rare in NLPHL and raises the possibility of THRLBCL if there are only CD57-negative T cells and no small B cells in the background. Cases of NLPHL with bone marrow involvement have been found to show aggressive clinical behavior (34, 35). Advanced-stage NLPHL responds poorly to chemotherapy regimens traditionally used for CHL, but responds better to R-CHOP, or regimens used for aggressive B-cell lymphomas (35).

Classical HL

Morphology and histology

Classical HL is characterized by the presence of typical HRSCs in a cellular milieu that varies depending on the histological type of CHL (1, 2). The neoplastic cells can sometimes become smaller due to apoptotic changes: they are accordingly termed “dwarfs” (1).

In LRCHL, growth may be either nodular or, more rarely, diffuse (1, 2, 36). The reactive component consists of small lymphocytes (mostly of B-cell origin) and some histiocytes with or without microgranuloma formation. In this context, HRSCs are scattered through the nodules or more rarely located at their periphery. Occasionally, residual germinal centers are seen within the nodules in an eccentric location. Neutrophils and eosinophils are absent. LRCHL was in the past included in the setting of LPHL based on purely morphological criteria (36). With the advent of immunohistochemistry, it became evident that the neoplastic cells had the typical phenotype of HRSCs and not LPCs (36, 28, 37). With the present therapeutic approaches, LRCHL has a more favorable course than the other types of CHL, similar to that of LPHL. Unlike LPHL, LRCHL rarely relapses (36).

NSCHL accounts for about 70% of CHL cases in Western countries, although its prevalence varies in different parts of the world (38). Conversely to the other types of CHL, it affects more often females than males and shows a mediastinal mass (with possible features of bulky disease) in 80% of patients (39). Morphologically, NSCHL is characterized by nodules surrounded by collagen bands that depart from a thickened lymph node capsule and turn birefringent in polarized light. The cellular composition of the nodules can significantly vary by mimicking one of the other types of CHL (LR, MC and LD). Occasionally, only nodule formation is seen with minimal or absent fibrosis: this pattern is termed the “cellular phase” of NSCHL (40). The neoplastic cells are mostly mononucleated and can acquire a “lacunar” appearance in improperly fixed material, consisting in the retraction of cytoplasm close to the nucleus with some thin connections to the cytoplasmic membrane, thus featuring the presence of lacunae (1, 2). According the British National Lymphoma Investigation (BNLI), 2 grades of NSCHL can be distinguished that potentially have prognostic relevance (41, 42). Grade I corresponds to the presence of a small amount of scattered HRSCs in a composite cellular milieu consisting of variable amounts of small lymphocytes, histiocytes, neutrophils, eosinophils, mast cells, and plasma cells. Grade II is presumed to be present if 1) more than 25% of the nodules show sarcomatous lymphocyte depletion; 2) more than 80% of nodules show features of the fibrohistiocytic variant; or 3) more than 25% of nodules show numerous bizarre, anaplastic-appearing HCs without lymphocyte depletion. If such criteria are followed, approximately 15% to 25% of NSCHL cases are classified as grade II. Grading is not mandatory for clinical purposes but has been applied during some clinical trials. However, its relevance is declining due to advances in therapy that blunt differences seen in less effectively treated patients (43, 44). Within the morphological spectrum of NSCHL, one should remember the so-called syncytial variant, which is characterized by large aggregates of neoplastic cells within the nodules, resembling metastatic involvement by undifferentiated carcinoma (45). Immunohistochemistry is pivotal in the differential diagnosis, as it is in the distinction of grade II NSCHL from ALK-negative anaplastic large cell lymphoma (ALCL) (see below).

In MCCHL, HRSCs can be easily found in a mixed reactive population composed of lymphocytes (mainly T), histiocytes, plasma cells, neutrophils, and eosinophils (1). There is complete effacement of the normal lymph node structure, at times with some spared follicles with germinal centers (1). The differential diagnosis should take into account peripheral T-cell lymphomas (PTCLs), especially of the T follicular helper (TFH) type, that can contain EBV-positive HRS-like cells (2); however, T lymphocytes in MCCHL show a complete T-cell phenotype and do not homogeneously express TFH-related markers conversely to those of TFH-PTCLs (2).

LDCHL includes 2 morphological subtypes (1, 2, 9). One shows a cellular milieu mostly consisting of fibroblasts and histiocytes (fibrohistiocytic variant). The other turns extremely rich in neoplastic cells and is accordingly termed “sarcomatous”. In the latter, neoplastic cells can form a palisade at the periphery of large necrotic areas and at times diffuse through sinuses. Immunophenotyping is of paramount importance for the differential diagnosis from ALK-negative ALCL (see below).


HRSCs of CHL have a distinctive phenotypic profile (1, 2). They strongly express CD30 with a characteristic dot-like and membrane-bound positivity that corresponds to the synthesis of the molecule in a proteic form (molecular weight 90 kD) in the Golgi apparatus and – following glycosylation (molecular weight 120 kD) – to its location at the cellular membrane level, where it acquires a transmembrane location (46-47-48). Importantly, although located on the external domain of CD30, the epitopes detected by Ber-H2 (which is the reference antibody for its immunohistochemical identification) and SGN30 (used for the construction of brentuximab vedotin) are not involved by the shedding phenomenon that makes CD30 detectable in the peripheral blood (49). This is quite important since CD30 does represent an important diagnostic and therapeutic target (49). In about 60% of cases, HRSCs express CD15, also known as X-hapten, with a staining pattern like that of CD30 (50). This is one of the many inappropriate molecules expressed by HRSCs: these include CD15, GATA3, TRAF1, ID2, ABF1, JUN, JUNB, AP-1, FLIP (CFLAR), JAK/STAT, STAT5 and the cytotoxic markers TIA-1, granzyme B and perforin in at least 20% of cases. All these aberrant attributes are thought to facilitate the immune escape of neoplastic cells (51-52-53-54). One of the main features of HRSCs is the fact that – despite their B-cell derivation – they show downregulation of the B-cell program and loss of most B-cell markers (see also molecular characteristics below) (55). In more than 90% of cases, they retain only the expression of the PAX5 product, also known as BSAP (B-cell-specific activator protein), although at a lower intensity than normal B cells. CD20 is expressed in about 30% of cases by a proportion of neoplastic cells with an intensity modulation (56). CD79a is detected in no more than 10% of cases with a staining pattern like CD20. The transcription factors BCL6, BOB.1, OCT-2 and PU.1 are usually absent (57). At times, either BOB.1 or OCT-2 may be singly present, yet not resulting in transcription of IG genes. CD45 and EMA are also defective. IRF4 is expressed by HRSCs in most if not all cases as well as the Ki-67 antigen (1). Despite the latter finding, HRSCs are characterized by abortive cytokinesis, entering the cell cycle but not proceeding through it (58). BCL2 and p53 are expressed by more than 50% and 25% of neoplastic cells in one third and 12% of cases, respectively (59). These figures are provided with prognostic relevance (59). In 87% of cases, HRSCs express CD274/PD-L1 and CD273/PD-L2, which can represent the rationale for the therapeutic use of immune checkpoint inhibitors (60). Finally yet importantly, in a small percentage of cases HRSCs express 1 or more T-cell-associated molecules (61). In some instances, the intracytoplasmic and globular positivity points to passive absorption. However, they are at times detected at the cytoplasmic membrane level. Most of the cases with this finding have been found to carry IGVH rearrangements with polyclonal T-cell receptors (TCRs) at polymerase chain reaction (see molecular characteristics below) (62).

In cases rich in neoplastic cells (NSCHL grade II or LDCHL sarcomatous), the differential diagnosis includes ALK-negative ALCL. Under these circumstances, the detection of PAX5, IGVH clonal rearrangement, lack of TCR clonality, and possible EBV infection point to CHL (1, 2).

The microenvironmental components also merit attention, not only for the cross-talk between them and neoplastic cells mediated by cytokines and cytokine receptors, but also for prognostic reasons. The content of macrophages (with cutoff values ranging from 5% to 25%), the subset of T lymphocytes, and the presence of myeloid suppressor cells have been found to be of potential prognostic value, although conflicting data have been reported in the literature (59, 63-64-65-66-67-68-69-70).

Agostinelli and coworkers (59) have studied many markers proposed as having prognostic value and referred to either HRSCs or the microenvironment, and compared them with the predictive value of interim positron-emission tomography (PET) scan (PET-2). In PET-2-negative patients, expression of CD68 (>25%) and programmed cell death protein 1 (PD1) (diffuse or rosetting pattern) in microenvironmental cells, and STAT1 negativity in HRSCs identified a subset of PET-2-negative patients with a significantly lower 3-year progression-free survival (PFS) rate than the remaining PET-2-negative population (p<0.0001) (59).

EBV infection

EBV infection of HRSCs can be demonstrated by EBER 1/2 in situ hybridization and the detection of LMP1 and EBNA1 (latency II pattern) on immunohistochemistry (71). The molecular test provides highly reliable results. LMP-1 expression is regarded as potentially implicated in the pathogenesis of the tumor because of its in vitro transforming capability (72). It is, in fact, possible that EBV infection of a B cell replaces one of the genetic alterations necessary for the development of CHL (73). The prevalence of EBV in HRSCs varies according to the histological subtype and epidemiological factors (73). The highest frequency (~75%) is found in MCCHL, and the lowest (10%-40%) in NSCHL (74). In resource-poor regions and in patients infected with HIV, EBV infection is close to 100% (75). The type of EBV strain also varies among geographical areas. In resource-rich countries strain 1 prevails, and in resource-poor countries strain 2.

Cell of origin

As previously mentioned, IGH gene rearrangement studies carried out by single-cell microdissection provided convincing evidence that HRSCs of CHL are clonal and derived from germinal-center B cells, even if they lack morphological or phenotypic similarities other than their PAX5/BSAP expression (5, 6, 55). In exceptional instances, HRSCs were reported to harbor clonally rearranged T-cell receptor genes, indicating that cases with morphological features of CHL might be derived from T cells (62, 76). This remains a still unsolved and challenging issue, since the boundary between these exceptional cases and PTCLs, especially ALK-negative ALCL, remains elusive.

Molecular characteristics

HRSCs show clonal IGVH rearrangements in more than 98% of cases (5, 6). As mentioned above, single-cell microdissection is required to detect clonal rearrangements in most instances, as DNA extracted from whole tissue tends to give poor results (5, 6). The rearranged IGVHs of tumor cells harbor a high load of somatic hypermutations, usually without signs of ongoing mutations (77, 78). These findings support the view that in most if not all instances HRSCs are derived from a germinal center B cell (77-78-79-80). Despite such derivation, HRSCs have lost much of the B-cell-specific expression program and have acquired B-cell-inappropriate gene products, as reported in the immunophenotype section (54). In addition, deregulated transcription factors in CHL promote proliferation and abrogate apoptosis in the neoplastic cells (81-82-83-84-85-86-87). The transcription factor NFκB is constitutively activated in HRSCs, and there is altered activity of the NFκB target genes, which regulate proliferation and survival, the AP-1 complex and the Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling pathway. Mutations of the JAK regulator SOC-1 are associated with nuclear STAT5 accumulation in HRSCs, indicating blockage of the negative feedback loop of the JAK/STAT5 pathway (88-89-90). Despite the possible overexpression of p53, mutations of TP53 are rare or absent in primary CHL tissue (91).

Classical cytogenetic and fluorescence in situ hybridization (FISH) studies show aneuploidy and hypertetraploidy, consistent with the multinucleation of the neoplastic cells; however, these techniques fail to demonstrate recurrent and specific chromosomal changes in CHL (92). Comparative genomic hybridization, however, shows recurrent gains of the chromosomal subregions on chromosome arms 2p, 9p and 12q and distinct high-level amplifications on chromosome bands 4p16, 4q23-q24 and 9p23-p24 (93). Special attention is due to alterations at 9p24.1, since this region includes the genes encoding for CD274/PD-L1, CD273/PD-L2 and JAK2, heralding sensitivity to specific targeted therapies (60).

Gene expression profile (GEP) studies have confirmed all these findings, including the global downregulation of the B-cell program, and have highlighted similarities between CHL and primary mediastinal large B-cell lymphoma (PMBL) (94, 95). Among these similarities are overexpression of the genes encoding for CD274/PD-L1, CD273/PD-L2 and JAK2 due to 9p24.1 alterations. The similarities between the CHL and PMBL signatures are not surprising, also in the light of a grey zone between the 2 neoplasms (1, 2). Interestingly, Tiacci and coworkers (96) reported that differences exist by profiling HL cell lines and microdissected HRSCs. In fact, analysis of the latter identified 2 molecular subgroups of CHL associated with differential strengths of the transcription factor activity of NOTCH1, MYC and IRF4. Moreover, HRSCs displayed deregulated expression of several genes potentially highly relevant to lymphoma pathogenesis, including silencing of the apoptosis inducer BIK and of INPP5D, an inhibitor of the PI3K-driven oncogenic pathway. Two further GEP studies, which were carried out in microdissected HRSCs and mRNA extracted from formalin-fixed, paraffin-embedded tissue blocks, highlighted some additional findings of potential prognostic value. In the former (97), a macrophage-like signature in HRSCs significantly correlated with treatment failure. CSF1R is a representative of this signature, and its expression was significantly associated with PFS and overall survival (OS) in an independent set of 132 patients assessed by mRNA in situ hybridization. A combined score of CSF1R in situ hybridization and CD68 immunohistochemistry was an independent predictor for PFS in multivariate analysis. In the other study (98), a 23-gene outcome predictor was generated. The model identified a population at increased risk of death in a validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups. The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.

Whole-exome sequencing on purified HRSCs has revealed inactivating B2M mutation as the most frequently detected gene mutation in CHL (99). This leads to loss of major histocompatibility complex class I (MHC-I) expression. The absence of B2M protein in HRSCs was also associated with lower stage of disease, younger age at diagnosis, and better OS and PFS. In a further study, Steidl and coworkers (100) showed in 15% of CHL cases the presence of fusions involving CIIITA (MHC II transactivator) and causing downregulation of human leukocyte antigen (HLA) class II expression and overexpression of CD274/PD-L1 and CD273/PD-L2.

Some novel gene loci have been identified as being linked to the risk of the development of CHL (101, 102). The association between rs6903608 and EBV-negative CHL was confined to the NS histological subtype. Other associations involving HLA class I have been identified in EBV-positive CHL, mainly the MC subtype (103). These observations confirm the relevance of histological subtyping of CHL, and differentiation between EBV-positive and EBV-negative cases (102).

Treatment of Hodgkin lymphoma

The historical perspective

Treatment of HL has evolved more rapidly than the understanding of the biology underlying this neoplasm, and Gianni Bonadonna with his group at the Istituto Nazionale dei Tumori of Milan (INT) has greatly contributed to the improvement of HL therapy, developing treatment strategies that still ensure the cure of at least 80% of all patients.

After the introduction of the MOPP regimen (mechlorethamine, vincristine, procarbazine and prednisone) in 1964 by De Vita and his group at the US National Cancer Institute in Bethesda (NCI), which transformed the treatment of advanced-stage HL from palliative to curative, the most important achievement was the development in 1973 at INT of the 4-drug ABVD regimen (adriamycin, bleomycin, vinblastine and dacarbazine) by Bonadonna (104, 105). ABVD was proven to be effective in patients failing MOPP and to yield superior efficacy results compared to MOPP when tested upfront in a randomized trial which also included radiation therapy (RT) in stage IIB and III. Moreover, ABVD was easy to administer, well tolerated and devoid of severe iatrogenic effects, in particular secondary leukemia and sterility, which occurred more frequently after treatment with MOPP (106-107-108-109-110). Based on these results, Bonadonna and his group compared MOPP to the monthly alternated MOPP and ABVD regimen (MM/AA) in stage IV HL patients, demonstrating the long-term superiority of the alternating drug combination over MOPP alone (111). The results of these studies were confirmed in a large randomized trial conducted by CALCG that showed superimposable cure rates for ABVD and MM/AA, and from that moment ABVD has become the treatment of choice for HL (112). The Italian investigators also explored different schedules of the alternating regimens for advanced-stage HL in order to overcome drug resistance by testing the Goldie-Coldman hypothesis, and to improve treatment outcome: they compared monthly alternated MM/AA to a more rapid alternation of a half cycle of MOPP and a half cycle of ABVD, the so-called hybrid MA/MA regimen, which, however, achieved equivalent cure rates (113). No new regimen was designed until 1989, when the Stanford group introduced Stanford V (doxorubicin, vincristine, mechlorethamine, vinblastine, bleomycin, etoposide and prednisone), a dose-intense, brief regimen given for 12 weeks followed by consolidation RT to sites of initial bulky disease, for unfavorable early- or advanced-stage HL. The aim was to improve the efficacy and decrease the risk of second malignancies, cardiopulmonary toxicity and sterility by reducing the cumulative exposure to alkylating agents as well as to anthracyclines and bleomycin, and by limiting the extent of radiation in combination with chemotherapy (CT) (114). The widespread adoption of Stanford V was limited, mainly because this regimen did not yield superior results when compared with ABVD in randomized trials (115). Another new regimen, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), was developed in 1994 by Diehl, the chairman of the German Hodgkin Lymphoma Study Group (GHSG). When employed with higher than standard doses in intensified escalated BEACOPP, this regimen yielded better tumor control and an increased OS at 10 years compared with the standard dose of BEACOPP and the alternated COPP (cyclophosphamide, vincristine, procarbazine and prednisone)/ABVD regimen in advanced-stage disease (116). Controlled randomized trials have been conducted to compare escalated BEACOPP with ABVD, confirming the advantages of escalated BEACOPP in terms of a significantly higher PFS rate, and its disadvantages, including grade 3-4 hematological toxicity and the risk of severe infections (both of which preclude its use in patients older than 60 years), as well as the risk of secondary leukemia and permanent sterility (117-118-119). Futhermore, for patients failing BEACOPP, the results of salvage high-dose chemotherapy (HDCT) and autologous stem cell support (ASCT) have been inferior to those in patients failing ABVD (116, 120). Recent studies conducted by GHSG in advanced-stage HL have attempted to decrease the toxicity of escalated BEACOPP by decreasing from 8 to 6 the total number of cycles administered and by limiting consolidation RT to residual adenopathies of at least 2.5 cm in diameter which were found to be metabolically active on PET scan performed after CT (121).

Another major achievement in the treatment of HL was the improvement in survival of patients with early-stage HL: 90% of these patients can nowadays be cured with a combined modality approach. Bonadonna was a pioneer also in this field: in 1990 he conducted a trial in patients with stage I and stage IIA favorable and unfavorable HL, omitting staging laparotomy and comparing a brief course of CT of 4 cycles of ABVD followed by subtotal nodal irradiation (STNI) (36 Gy to involved and 30 Gy to uninvolved nodal sites) with the same CT followed by less extensive radiation, namely only 36-Gy involved-field (IF) RT (122). The results of this study documented that a limited number of ABVD cycles followed by IFRT was a safe and effective approach and recently updated results have confirmed excellent long-term outcome with 20-year freedom from progression and OS of 90.8% and 88.8%, respectively, compared to 95.2% and 78% for patients receiving STNI after 4 ABVD cycles (122). In an attempt to reduce toxicity while maintaining a high cure rate, the GHSG investigators proved that for favorable early-stage HL, as defined by the absence of a bulky mediastinal mass or extranodal involvement, the presence of fewer than 3 involved sites and ESR <30 in case of B symptoms or <50 in case of A symptoms, only 2 cycles of ABVD followed by 20 Gy IFRT were the treatment of choice, yielding superimposable results to 4 cycles of ABVD and 30 Gy (123).

Provocative findings were reported by a study started in 1994 that aimed to evaluate whether RT could be eliminated, without significantly impairing OS, in order to avoid late adverse events, namely second cancers and cardiac disease. Patients with stage I-IIA non-bulky HL were randomly assigned to receive ABVD alone for 4 to 6 cycles or STNI, eventually combined with 2 ABVD cycles. ABVD alone was associated with a 12-year failure-free survival of 86%, and, more relevantly, with a higher OS rate of 94% due to a lower rate of deaths from causes other than HL as compared with 87% for the treatment that included radiation (124). Although STNI is no longer considered an adequate RT treatment and the combined modality treatment with a limited extent of RT delivered at lower doses was proved to yield high cure rates, the question of determining whether RT could be avoided without detrimental survival results, as just occurred in the treatment of children with early-stage HL, is still intriguing.

The contemporary perspective

Contemporary efforts in HL treatment are directed towards reducing acute and late toxicity rather than increasing the cure rate. Better risk stratification and mainly, starting in the mid-1990s, the use of PET with 18F-fluorodeoxyglucose (FDG) as an early indicator of chemosensitivity have guided the modulation of therapy in advanced- as well as early-stage HL. In advanced-stage HL, patients with a PET scan after the first 2 ABVD cycles (PET-2) scored as Deauville (DS) 4, conventionally defined as lesions with an uptake more intense than the physiological uptake in the liver, and those with DS 5, defined as lesions with a very intense uptake or appearance of new FDG-avid lesions, have a high probability (72%-87%) of treatment failure on continuing ABVD (125). On the other hand, intensifying treatment by shifting to escalated BEACOPP may overcome the negative prognostic impact of PET-2 positivity. The RATHL phase III study, enrolling 1,214 patients, documented 3-year PFS and OS rates of 67.5% and 87.8%, respectively, for PET-2-positive patients who were switched from ABVD to escalated BEACOPP. Moreover, the study demonstrated that it is safe to de-escalate from ABVD to AVD (adriamycin, vinblastine, dacarbazine) for PET-2-negative patients, reducing pulmonary toxicity by omitting bleomycin, with superimposable 3-year PFS: patients receiving 4 more cycles of AVD achieved a 3-year PFS of 84.4% compared with 85.7% for patients receiving 4 ABVD cycles (126). The efficacy of response-adapted therapy for advanced-stage HL, switching from ABVD to more intensified treatment such as 6 cycles of escalated BEACOPP or 4 cycles of escalated BEACOPP followed by 4 cycles of standard-dose BEACOPP, or finally switching to high-dose CT and ASCT, was confirmed in several trials (127-128-129). A major limitation of all these studies is related to their comparison with historical series instead of a randomized comparison of continuation of ABVD versus intensified CT in PET-2-positive patients. However, the reported poor prognosis of this group of patients when continuing on the ABVD regimen makes it hardly acceptable to conduct such a phase III study for ethical reasons; careful and prolonged follow-up of the above-mentioned trials could offset these limitations and provide further support to this strategy.

PET-adapted therapies have been evaluated to individualize treatment in early stages as well. The RAPID trial randomly assigned patients with stage IA-IIA non-bulky HL to receive IFRT or no further treatment if after 3 cycles of ABVD the PET scan was negative, with DS 1 or 2, defined as an uptake equal to or lower than that in the mediastinal blood pool. On the other hand, patients with a DS 3-5 PET scan received an additional ABVD cycle followed by IFRT. In the 209 patients with a negative PET scan undergoing IFRT, the 3-year PFS was 94.6% compared with 90.8% (95% confidence interval [CI] -8.8 to 1.3) for the 211 patients receiving no further treatment (130). As the study was designed to detect a non-inferiority margin of 7%, the values of the 95% CIs for the difference exceeded that margin and the results of the study were considered negative. Nevertheless, the prognosis of PET-negative patients in whom RT was omitted is very good, with a low risk of relapse (below 10%) and an expected lower risk of late cardiac and carcinogenic complications. Similar conclusions can be drawn from the results of another PET-adapted phase III study for patients with stage I-II favorable or unfavorable HL who achieved a negative PET result after 2 cycles of ABVD: in these patients the omission of involved-nodal (IN) RT was randomly compared with a standard combined-modality approach (131). Based on the results of the interim analysis after a median follow-up of 1.1 year, which documented a significantly higher number of events in the no-RT arms, the experimental arms were prematurely closed and all patients continued treatment receiving INRT. Nevertheless, in both favorable and unfavorable presentation, the 1-year PFS difference for PET-2-negative patients omitting RT compared to those receiving INRT was small, namely 94.9% versus 100% in the favorable group, and 94.7% versus 97.3% in the unfavorable group, respectively. Only longer follow-up will tell us whether the real but small PFS advantage will be worth pursuing or will be offset by later fatal complications in the radiation arm. Radiation oncologists have nicely refined RT planning and delivery techniques: nowadays they are able to deliver RT to limited fields that include only the involved lymph nodes as defined by staging CT and PET scan. Based on the quality of these imaging techniques they can adopt INRT when staging imaging is performed with the patient in the treatment position, or, if this is not feasible, with the involved site (IS) encompassing extra margins added to the clinical target volume to compensate for uncertainties associated with suboptimal imaging (132). In any case, modern RT allows to erogate lower doses of radiation to surrounding normal tissues, and this will hopefully prove to decrease late complications.

The future perspective

Further advances in the treatment of HL are expected by the introduction of new exciting drugs that have been discovered and recently evaluated in the setting of relapsed and refractory HL: the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) and the immune checkpoint inhibitors nivolumab and pembrolizumab.

BV is an anti-CD30 chimeric IgG1 antibody conjugated to the antitubulin agent monomethyl auristatin E (MME). After binding to CD30-expressing cells such as HRSCs, the complex is internalized and free MME is released by proteases into the cytoplasm; thereafter MME binds to the microtubules and inhibits their polymerization, inducing cell cycle arrest and finally cell death due to apoptosis (133). In a pivotal phase II trial evaluating BV at the dose of 1.8 mg/kg in 102 patients with relapsed or refractory HL after ASCT, an overall response rate (ORR) of 75% and a complete remission (CR) rate of 34% were reported (134). Furthermore, after 5 years of follow-up 9% of all enrolled patients were in continuous CR without any further teatment (135). The main toxic effects were peripheral sensory neuropathy, which resolved after stopping therapy in the large majority of cases, nausea, fatigue and diarrhea. When given as consolidation treatment after ASCT in patients at high risk of failing ASCT in the phase III AETHERA trial, BV significantly improved PFS compared with placebo: at 3 years, PFS was 61% in the BV arm and 43% in the placebo arm. The greatest benefit was in patients with at least 2 risk factors including short duration (less than 12 months) of first CR or refractoriness to frontline therapy; extranodal disease and/or B symptoms at relapse; partial remission or stable disease after salvage therapy; and 2 or more salvage therapies. This held true also for those patients with a negative PET scan before receiving ASCT (136, 137). No benefit in OS has been observed so far, as patients who experienced relapse in the placebo arm were then treated with BV, followed in selected cases by allogeneic transplant.

Due to its high efficacy in the post-ASCT relapse setting, BV was moved forward and is now under evaluation in combination with several CT regimens as first-line salvage therapy before ASCT. One of the most promising regimens is the combination of BV (1.8 mg/kg on day 1) with bendamustine (90 mg/m2 on days 1 and 2) given every 3 weeks for up to 6 cycles, which induced a very high response rate in 53 evaluable patients with primary refractory HL or in first relapse of HL. The ORR was 93% and 74% of patients who achieved a CR; stem cell mobilization was reported in 95% of patients; toxicity was acceptable and mainly represented by infusion-related reactions, which caused therapy discontinuation, despite corticosteroid and antihistamine premedication, in 7% of cases. After a minimum of 2 cycles patients could undergo ASCT; the 2-year overall PFS was 61% for the entire series and 68% for those patients who underwent ASCT (138). These response rates are among the highest ever seen in relapse/refractory settings.

BV has also been introduced in the upfront setting of advanced- as well as early-stage HL with different endpoints. BV (0.6-1.2 mg/kg) was given combined with ABVD or AVD in a phase I study to 51 untreated advanced-stage patients: the combination of BV and ABVD was complicated by severe and even fatal pulmonary toxicity, leading to the conclusion that administering BV concomitantly with bleomycin is contraindicated. The combination of BV with AVD (A-AVD) achieved promising results with 3-year PFS and OS rates of 96% and 100%, respectively (139, 140). A-AVD given for 6 cycles is now being tested against ABVD in an ongoing randomized international phase III trial (ECHELON-1) for stage III and IV HL: the study has recently completed enrollment and the results, which have the potential to change clinical practice, are awaited with great interest.

BV (1.8 mg/kg) has also been incorporated into a modified BEACOPP regimen, the so-called BRECADD, in which, in order to reduce acute and late toxicity (mainly secondary leukemia, sterility, pulmonary dysfunction and neuropathy), bleomycin and procarbazine are omitted, vincristine is replaced with BV, lower doses of etoposide are used, and dexamethasone is delivered for 4 days instead of 14-days administration of prednisone. Preliminary results of a phase II study have shown that BRECADD is effective: 95% of patients achieved CR, and this result compares favorably with historical data on escalated BEACOPP, while the toxicity is less pronounced (141).

In early-stage HL BV has been introduced to avoid RT or to evaluate safety and possibly increase efficacy. In 34 patients with stage I-II non-bulky HL, BV (1.2 mg/kg) was given as a leading course for 2 doses, followed by A-AVD for a total of 4 or 6 cycles according to the PET results after the first 2 A-AVD cycles. In this small case series, 1 patient died due to neutropenic sepsis and 1 discontinued therapy because of a hypersensitivity reaction; among 32 evaluable patients who had received a total of 4 cycles, the CR rate was 91%, and 1-year PFS and OS were 94% and 97%, respectively (142).

In 30 patients with early-stage unfavorable-risk HL, A-AVD given for 4 cycles followed by 30 Gy ISRT, delivered using the deep inspiration breath-hold technique to spare normal lung and heart tissue, has also been tested. In this pilot study 90% of patients achieved a negative PET result after 2 cycles of A-AVD, and after a median follow-up of 18.8 months the preliminary results showing 1-year PFS of 93.3% seem promising (143). No clinically significant drug-related pulmonary toxicity was observed, with the exception of a mild reduction of diffusing capacity for carbon monoxide (DLCO) after A-AVD, which did not worsen after ISRT and improved after 12 months’ follow-up.

Only randomized trials and long-term follow-up evaluating risks and benefits will allow to define the role of BV given as a single agent or in combination in the frontline setting.

Furthermore, BV may be an option for elderly patients who are not suitable candidates for conventional CT due to comorbidities, which may increase teatment-related toxicity and require treatment delay or dose reduction, contributing to the inferior prognosis of advanced-stage HL patients aged over 60 compared with their younger counterparts. In these patients BV as a single agent (1.8 mg/kg every 3 weeks for up to 12 cycles) was active, inducing 92% ORR and 73% CR with a median PFS of 10.5 months (144). Combinations of BV (1.8 mg/kg every 3 weeks for up to 12 cycles) with dacarbazine (375 mg/m2) or bendamustine (90-70 mg/m2 on days 1 and 2) were able to induce very high response rates: in patients treated with BV plus dacarbazine the ORR was 100% (62% CR), and in those treated with BV plus bendamustine the ORR was 100% (78% CR). The toxicity profile was acceptable, with peripheral neuropathy, fatigue, nausea, peripheral edema, diarrhea and decreased appetite being most frequently reported; however, the combination of BV and bendamustine was not well tolerated in a fragile elderly population, with 65% of patients experiencing grade 3 or higher adverse events. Follow-up is still too short to draw any conclusions on the durability of the efficacy of these combinations and larger studies are warranted to confirm these preliminary encouraging results (144).

Among the monoclonal antibodies, a new bispecific tretravalent chimeric anti-CD30/CD16A antibody construct, which recruits and activates natural killer (NK) cells that mediate tumor cell lysis, AFM13, is now under evaluation in HL (145).

Another exciting field of research in HL are immune checkpoint inhibitors such as the monoclonal antibodies nivolumab and pembrolizumab. PD1 acts as an immune checkpoint to mediate immune functions. When the programmed cell death ligands 1 or 2 (PD-L1 or PD-L2) bind to the PD1 receptors on T and NK cells, they inhibit their activation, thus inducing immune effector cell tolerance and permitting tumor cells to escape the mechanisms of immune surveillance. HRSCs overexpress PD-L1 and PD-L2; furthermore, the microenvironment that surrounds HRSCs is constituted by reactive and inflammatory immune cells, among which are immunosuppressive tumor-associated macrophages that also overexpress PD-L1 and PD-L2. Therefore, monoclonal anti-PD1 antibodies, that block the interaction between PD1 and PD-L1 or PD-L2, restore the anticancer immune response. Nivolumab and pembrolizumab, which block the interactions beween PD1 and its ligands, have been tested in clinical trials in HL with very interesting results. Nivolumab, a fully human IgG4 monoclonal antibody targeting the PD1 receptor, given at 3 mg/kg every 2 weeks for up to 24 months was evaluated in a phase I study involving 23 HL patients who had relapsed after ASCT, BV or at least 3 prior therapies. The safety profile was acceptable, with fatigue, diarrhea and infusion reactions being the most commonly reported adverse events; grade 3-4 colitis, pneumonitis, cytokine release syndrome, and increased amylase and lipase have also been reported, as when the antibody is used in solid cancers. In this heavily pretreated patient population ORR was 87% and CR 17% (146). Subsequently, a large international phase II study confirmed these high response rates among 243 patients failing ASCT, pretreated or not with BV. Similar results were reported with pembrolizumab, a humanized monoclonal IgG4 antibody directed against the cell surface receptor PD1, given at a flat dose of 200 mg every 3 weeks in a phase II study enrolling 3 cohorts of patients: relapsed or refractory patients who had failed ASCT and subsequent BV (cohort 1), patients who were ASCT-ineligible due to chemoresistance and BV failure (cohort 2), and patients who had failed ASCT but were not pretreated with BV (cohort 3). ORR was 73% in cohorts 1 and 3, and 83% in cohort 2; CR was 27% in cohort 1, and 30% in cohorts 2 and 3 (147).

Everolimus, an antineoplastic agent targeting the mTOR complex 1, given orally at 10 mg daily, has also shown activity in relapsed/refractory HL, inducing 47% ORR and 5% CR among 19 patients, and clinical trials evaluating the combination of everolimus and BV are currently ongoing (148).

Another promising approach is targeting the PI3 kinase pathway and JAK-stat pathway, which can result in modulation of the microenvironment and translate into tumor regression, as shown by the encouraging results of a phase I study utilizing a PI3 kinase delta inhibitor in combination with a selective JAK1 inhibitor, where an ORR of 67% was obtained (149).


The development of the present concept of HL took about 2 centuries. Treatment of HL has improved substantially over the past 30 years, and the reduction of long-term toxiciy in early-stage HL and improvement of the results in advanced-stage HL have enabled the majority of patients to achieve cure. The discovery of targets and pathways has allowed the development of new drugs with exciting high response rates and favorable toxicity profiles. Despite the many new pieces of information available, we have not reached the final goal. In fact, we still need to ascertain which patients might need a less toxic approach and which patients will be relapsing early or become resistant to therapy. Once these elements will be defined before the start of therapy, the long journey begun by Sir Thomas Hodgkin will possibly be concluded.


Financial support: The manuscript was supported by the grant “AIRC 5 × 1000”, No. 10007 to SAP.
Conflict of interest: None of the authors has any conflict of interest related to this article.
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  • Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
  • Unit of Hematopathology, European Institute of Oncology, Milan - Italy
  • Bologna University School of Medicine, Bologna - Italy

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