Nodular lymphocyte-predominant Hodgkin lymphoma

Author’s Accepted Manuscript Nodular lymphocyte lymphoma

predominant

Hodgkin

Kerry J. Savage, Anja Mottok, Michelle Fanale

www.elsevier.com/locate/enganabound

PII: DOI: Reference:

S0037-1963(16)30046-4 http://dx.doi.org/10.1053/j.seminhematol.2016.05.009 YSHEM50886

To appear in: Seminars in Hematology Cite this article as: Kerry J. Savage, Anja Mottok and Michelle Fanale, Nodular lymphocyte predominant Hodgkin lymphoma, Seminars in Hematology, http://dx.doi.org/10.1053/j.seminhematol.2016.05.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Nodular lymphocyte predominant Hodgkin lymphoma Kerry J. Savage1, Anja Mottok2 and Michelle Fanale3

1

Department of Medical Oncology, Centre for Lymphoid Cancer, British

Columbia Cancer Agency 2

Centre for Lymphoid Cancer, British Columbia Cancer Agency

3

MD Anderson Cancer Centre

Corresponding Author: Kerry J. Savage MSc MD 600 West 10th Avenue Vancouver, BC, Canada V5Z 4E6 Phone: 604 877 6000 Fax: 604 877 0585 [email protected]

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Introduction

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL), accounting for 5% of all HL. Patients with NLPHL typically present with asymptomatic early stage disease with peripheral lymph node involvement. Unlike classical Hodgkin lymphoma (cHL), late and often multiple relapses have been widely reported (1) but despite this, the prognosis is generally favourable with deaths due to NLPHL extremely uncommon. Due to disease rarity, information on the natural history of NLPHL and appropriate management is mostly ascertained from retrospective series or the evaluation of subsets enrolled in larger randomized controlled HL trials with very few prospective studies. After 1993, EORTC-GELA (European Organization for Research and Treatment of Cancer–Groupe d’Etude des Lympomes de l’Adulte) study groups excluded NLPHL from larger HL clinical trials and a separate clinical registry was created. In contrast, NLPHL patients have typically been included as part of the GHSG (German Hodgkin Study Group) trials.

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Pathology of NLPHL

NLPHL is characterized by a nodular or nodular and diffuse growth pattern with scattered large neoplastic cells originally referred to as lymphocytic and/or histiocytic Reed-Sternberg cell variants (L&H cells). In the updated 2008 World Health Organization (WHO) classification the malignant cells were re-named as lymphocyte predominant (LP) cells and, due to the characteristic multi-lobated or folded appearance of the nucleus, they are often referred to the descriptive term ‘popcorn’ cells (2). Surrounding the tumour cells are CD4+ T-lymphocytes that show typically a follicular helper T cell phenotype with co-expression of CD57 and PD1 (3, 4), supporting derivation of this lymphoma from the germinal centre (GC). Furthermore, cases with cytomorphologic atypical T cells, mimicking PTCL (peripheral T-cell lymphoma)-NOS, have been described that behave clinically similar to TCRBCL (T-cell rich B-cell lymphoma)-like NLPHL (5). The importance of pathologic review of older cases was highlighted from the European Task Force Study where only 56% of submitted cases of presumed NLPHL were confirmed by todays diagnostic standards (6).

In contrast to the Hodgkin and Reed-Sternberg (HRS) cells in cHL which express CD15 and CD30, LP cells are usually negative for these antigens and retain instead expression of B-cell markers including CD20 and CD79a as well as CD45 and epithelial membrane antigen (EMA)(2) (see Table 1). Moreover, LP

3

cells usually express the B cell transcription factors OCT-2 and BOB.1 (7) and are positive for BCL6 and activation-induced cytidine deaminase (AID) further emphasizing the GC origin although CD10 is largely negative (8). However, despite the fact that most of the classical B cell markers maintain expression, it has been shown that several B cell genes (e.g. CD19, CD37, LCK) are downregulated in LP cells contributing to a partial loss of the B cell phenotype (9) (10). Epstein Barr Virus (EBV) is typically negative.

A more detailed characterization of histopathological variants of NLPHL has been provided by Fan et al. (11) who described six immunoarchitectural growth patterns (Figure 1). Typical histologic growth patterns include classic nodular B cell rich (pattern A) and serpiginous/interconnected nodular (pattern B) types, both of which demonstrate a predominantly nodular growth with non-neoplastic B-cells and LP cells located within the nodules (Figure 1). In contrast, the socalled histopathologic variants have LP-cells outside the nodules and/or reduced B-cells within the nodules and include the following four patterns: nodular with predominance of extranodular LP cells (pattern C), nodular T-cell rich (pattern D), diffuse TCRBCL-like (pattern E), and diffuse (B-cell rich) moth-eaten (pattern F) (Figure 1). Of importance, a mixture of patterns was more often seen than pure patterns and about 8% of cases did not have a classical nodular pattern, highlighting the importance of recognizing variant growth patterns for rendering the diagnosis of NLPHL.

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Although the number of cases with available clinical data was limited in this initial study, it was noted that a diffuse TCRBCL-like pattern was associated with a higher rate of recurrent disease. More recently, the GHSG evaluated the prognostic significance of these histological variants in over 400 NLPHL patients and demonstrated that the histological variant group (patterns C-E above) was associated with a higher stage at presentation (29.5% vs. 14.6%) and a higher relapse rate (12).

Molecular signature of NLPHL Dysregulation of signaling pathways A common feature of cHL and NLPHL is frequent aberrant activation of the JAKSTAT-signaling pathway, in part due to inactivating mutations of the negative regulator SOCS1 (13) (14), which in LP cells results in nuclear accumulation of pSTAT6. Gene-expression based studies further revealed strong overlap with cHL with an upregulation of NFB target genes (9), however, unlike in cHL, mutations in NFKBIA and TNFAIP3, encoding for the NFB pathway inhibitors IB and A20, respectively, rarely occur in NLPHL (15). Genomic alterations The most common structural genomic alteration described in NLPHL is translocations of BCL6, occurring in about 50% of cases and either involving the Ig heavy chain locus or other genes (16). The paucity of tumour cells in

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conjunction with the rarity of NLPHL has largely precluded a comprehensive exploration of the mutational landscape in this disease. Hartmann et al. recently reported on whole genome sequencing of the DLBCL component of two composite NLPHL/DLBCL cases and subsequent targeted re-sequencing of 62 genes on whole tissue sections from 16 cases of an extension cohort (17). Novel recurrent mutations in DUSP2, SGK1 and JUNB (each of these genes mutated in about 50% of cases) were identified, in addition to mutations affecting known oncogenes or tumour suppressor genes such as, TP53, BRAF, PTPN1, ATM, BCOR and EP300. Since the mutations were seemingly enriched in the transformed lymphomas or in NLPHLs presenting with a variant histopathological growth pattern, it remains unclear to what extent these alterations truly reflect the biology of classical NLPHL or if they rather represent genomic aberrations associated with a more aggressive disease behaviour.

Relationship to other pathological entities Progressive transformation of germinal centres (PTGC) Progressive transformation of germinal centres (PTGC) is a benign condition characterized by enlarged follicular structures with expanded mantle zones, the latter often intruding into the GC. Although large centroblasts as well as higher numbers of CD4+CD57+ and CD4+CD8+ T cells can be found, PTGCs lack typical LP cells and T cell rosettes (18).

PTGC can occur prior to, concurrent

with, or after the diagnosis of NLPHL in patients (19) (20)

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NLPHL and T cell rich B cell lymphoma The distinction between TCRBCL-like NLPHL (Fan pattern E) and TRCBCL is difficult because there is considerable diagnostic overlap. Both lymphoma types share the rarity of tumour cells, which present with a similar immunphenotype (9) (Table 1). In addition PD1+ rosetting T cells are less frequently observed in diffuse areas of NLPHL (21) and can be present in TCRBCL. According to the current WHO classification one nodule of typical NLPHL in an otherwise diffuse infiltrate is sufficient to exclude a primary TCRBCL – posing a problem when dealing with small biopsies in the diagnostic setting. Cases of NLPHL with TCRBCL areas are not felt to represent a transition to TCRBCL and should be distinguished from de novo TCRBCL (2), however bonafide NLPHL and TCRBCL can occur synchronously or metachronously (22). Early

studies

using

classic

comparative

genomic

hybridization

(CGH)

demonstrated higher copy number (CN) alterations in NLPHL compared to TCRBCL (23), however, a more recent analysis employing array-based CGH (24), allowing for the detection of smaller alterations on microdissected tumour cells, revealed a higher percentage of genes with genomic aberrations in TCRBCL. Classical NLPHL, TCRBCL-like NLPHL and TCRBCL share a number of CN variations, including gain of 2p16.1, and losses of 2p11.2 and 9p11.2, suggesting a close relationship of these clinically different diseases (24).

By gene expression profiling only marginal differences between LP cells of classical and variant NLPHL and B blasts in TCRBCL have been observed (9)(25)

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In contrast, remarkable differences in the composition of the microenvironment exist with higher numbers of CD4+ follicular T helper cells in NLPHL, more CD163+ macrophages in TCRBCL-like NPLPHL and TCRBCL, as well as a higher content of cytotoxic T cells in TCRBCL (25, 26).

Transformation to aggressive non-Hodgkin lymphoma In addition to the biologic continuum of NLPHL and TCRBCL, it has long been recognized that there is an inherent risk of developing secondary aggressive non-Hodgkin lymphoma (NHL) in NLPHL with rates ranging from 0-17%, with higher frequencies observed in more mature studies with longer follow-up and those that have included more advanced staged patients in approximately (27-31) (reviewed, reference 31). This is in stark contrast to cHL where rates of only 0.93% are observed (32).

In studies that have evaluated risk factors for

transformation, higher rates were noted in patients with advanced stage and with intra-abdominal and/or spleen involvement at diagnosis (27, 30). In addition, advanced stage and involvement of the liver and spleen are common at the time of transformation which is of interest given similar observations in TCRBCL (27, 33). A clonal relationship between NLPHL and secondary DLBCL has been previously demonstrated (34) (22, 35).

Whether this represents a true

‘transformation’ from underlying NLPHL or rather a lymphoma arising by divergent evolution from a common precursor cell is still a matter of debate. In cases of TCRBCL following NLPHL (Figure 2), it is unclear whether NLPHL and TCRBCL represent a spectrum of the same disease and originate from the same

8

neoplastic clone or whether TCRBCL has evolved or transformed from NLPHL. The consensus for the upcoming revision of the WHO (2016) classification is that such cases should be referred to as TCRBCL-like transformation of NLPHL (E. Jaffe,

personal

communication).

Regardless,

the

outcome

following

transformation is favourable with 5 year overall survival (OS) estimates of  60% across studies (27, 28)(31).

Management of NLPHL: General Principles and Guidelines

Given disease rarity, there are no randomized controlled studies and few prospective studies to guide treatment recommendations and as result, guidelines are diverse and also differ in the pediatric/adolescent (up to age 21 years) and adult patients. The European Society for Medical Oncology (ESMO) guidelines are largely based on GHSG studies (36) and the National Comprehensive Cancer Network (NCCN) guidelines are based on retrospective studies and a minority of prospective studies (http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site)(Table 3).

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Management of Limited Stage NLPHL

It has been the subject of debate whether NLPHL patients should be treated differently from cHL and they are often included in broader trials in HL. Given the excellent prognosis of these patients, the focus has been limiting both acute and long-term toxicity. Further, the definition of limited stage also differs across guidelines with ESMO/GHSG/EORTC dividing all HL patients into favourable and unfavourable subgroups depending on the presence or absence of defined risk factors whereas many North American centres consider patients with bulky disease (stage 1 and 2) and/or B symptoms (stage 2) as having advanced stage. For the purposes of this review, limited stage will be confined where possible to those with non-bulky stage 1A/B or 2A disease and comparable to favourable risk groups by the EORTC and GHSG definitions.

Front-line management of limited stage NLPHL: Radiotherapy, combined modality therapy or chemotherapy alone? Multiple retrospective studies have reported outcomes for RT as a single modality for the management of limited stage NLPHL. Many of the series span decades but not all have undergone rigorous pathologic review using modern diagnostic criteria. Lessons from the European Task Force of Lymphoma (ETFL) (6) support that expert hematopathology review is mandatory. In addition, the re-

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review of cases diagnosed before routine immunophenotyping and mature follow-up is imperative to make accurate statements about natural history and the impact of various therapeutic approaches. Further, due to small patient numbers, many analyses combine stage 1 and 2 as well as results across treatment approaches (Table 4). With variable definitions of limited stage, across all studies, the 10-year OS ranges from approximately 85% to 100% and the failure rate with RT ranges from approximately 20% to 35% and 10-15% if stage IA is evaluated separately (Table 4). The most mature retrospective series evaluating RT alone described the outcome of 202 patients with stage I/II NLPHL diagnosed between 1969 and1995 but older cases were not re-reviewed. With a median follow-up of 15 years, the 15-year OS was 83%, freedom from progression (FFP) was 82% and outcome was superior in stage 1 patients (84% vs 73%, P=0.031)(37). There were a total of 41 deaths, 5 were from NLPHL and 17 were potentially linked to the RT (8 in field malignancies and 9 in field cardiac and respiratory disease); however, larger doses and fields would have been used in earlier treatment eras (37). Chen et al. evaluated 113 patients with early stage NLPHL (stage I=71, stage II=42), including some pediatric cases (38). The majority of patients were treated with RT alone at doses of 36-38 Gy with regional or extended fields. With a median follow-up of 11.3 years, similar outcomes were reported with stage I patients faring better than stage II (10 year PFS 89% vs 72%) treated with RT alone. Secondary malignancies were again found to be the main cause of death (38).

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In recent years, radiation doses and fields have been reduced to minimize the risk of secondary treatment complications; however, the risk with modern RT remains largely unknown given the long lag time before these complications develop. Secondary cancers are typically reported at least ten years after RT is administered (39). Efficacy appears to be preserved moving from extended field subtotal nodal RT to IFRT for the treatment of early stage HL(40). Further, restricting the RT field margin to ‘involved-nodal’ RT (< 5cm margin) does not appear to increase the risk of relapse in early stage HL when combined with chemotherapy (41) but whether this applies to use of RT alone is unknown. The large randomized HD10 GHSG study in favourable early stage HL, including NLPHL it was established that the IFRT dose can be reduced from 30 Gy to 20 Gy when combined with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) without compromising efficacy. This approach may reduce secondary malignancies; however, much longer follow-up is needed (42). However, when used as a sole modality, a dose of 30Gy is recommended with IFRT (ESMO)(30-36Gy NCCN) with all suspected subclinical disease be encompassed and thus as a minimum, adjacent tissues with generous margins (36, 43, 44).

In recent years, CMT has surpassed RT alone as the treatment choice for early stage HL due to an improvement in FFTF incorporating ABVD-equivalent regimens (45, 46). In addition to defining the optimal dose of RT in CMT, HD10 also established that 2 cycles of ABVD achieved similar outcomes to 4 cycles.

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In this study, overall, the 5-year relapse rate was < 10%, establishing a new benchmark for stage I/II very favourable HL. The successor randomized trial HD13 aimed to evaluate whether components of ABVD can be omitted without compromising efficacy in early stage HL (47). This important study demonstrated that dacarbazine is a vital component of ABVD. Further, omission of bleomycin also results in a slight absolute decrease of the 5 year FFTF (-3.9%, CI -7.7 to 0.1) but with similar OS. Despite the inclusion of NLPHL patients in these prospective randomized controlled trials, the results have largely only been applied to cHL. With favourable outcomes in NLPHL, there has been a reluctance to incorporate chemotherapy into treatment protocols due concerns of over-treating low risk patients in part a reflection of the absence of risk factors. Interestingly, a comparison of limited stage cHL without mediastinal involvement and limited stage NLPHL revealed no survival differences (48). Similarly, the GHSG found no difference in the risk of death or relapse between cHL and NLPHL when outcomes are compared within the stratified early favourable and early unfavourable risk groups (49). There have been few mature studies in adults with limited stage NLPHL comparing the outcome of CMT to RT alone. The German Hodgkin Study Group (GHSG) evaluated the outcome by treatment modality specifically in stage IA patients (n=257) with NLPHL who had been enrolled on prospective GHSG clinical trials from 1988 to 2007 (50). Four treatment groups were evaluated: extended field RT (EFRT) n=49; involved field RT (IFRT) n=108; combined-

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modality treatment (CMT) n=27; 4 weekly rituximab (50). The median follow-up for the respective groups were, 110 months, 87 months, 95 months and 49 months. Excluding the rituximab treated groups, the 8 y PFS (EFRT 84.3%; IFRT 91.9%; CMT 88.5% (95% CI, 80.3% to 96.8%) and 8 y OS (EFRT 95.7%; IFRT 99.0%; CMT 98.6% (95% CI, 86.5% to 97.3%) were similar (50).

In a report from the BCCA, the outcome of limited stage NLPHL patients treated in an era where RT alone was routine was compared to those treated in an era where ABVD chemotherapy was endorsed for all limited stage HL patients (51). Patients treated in the chemotherapy treatment era had a superior 10-year time to progression (TTP) (98% vs 76%, P=0.0074) and PFS (P=0.0024) with a trend observed for an improved OS (93% vs 85%, P=0.074). Most patients treated with chemotherapy received ABVD for 2 cycles followed by RT (51). In comparison to the GHSG study comparing RT to CMT (50), the BCCA analysis included non-bulky stage IIA patients but the results also support excellent outcomes with combined modality therapy in limited stage patients. Similar comparisons of the outcome of RT alone to CMT have been performed in several other retrospective series with mixed results (Table 4). Many of the studies treated very few patients with chemotherapy and do not have clear criteria as to why chemotherapy alone was selected. The MDACC compared the outcome of 37 patients with stage I/II disease NLPHL treated with RT with 11 patients treated with CMT using MOPP (mechlorethamine, vincristine, procarbazine and prednisone) or NOVP (mitoxantrone, vinblastine, vincristine

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and prednisone (52). There was no difference in the 10 year relapse free survival (RFS) (77% vs 68%, P=0.89) or OS (90% vs 100% P=0.43) for RT alone and CMT respectively but there was a disproportionate number of patients with stage II disease treated with CMT and the chemotherapy regimens are not standard today. In contrast, a recent retrospective study from the LYSA group evaluated the outcome of 63 primarily limited stage NLPHL patients treated with RT (stage I n=42, stage II n=20, stage III n=1) (65% supradiaphragmatic; 35% infradiaphragmatic) and 40 patients treated with CMT and the 4 y PFS favoured the CMT group 93.9% vs 79.6% (53). Relapses in the RT alone group occurred primarily outside of the RT field but due to small patient numbers stage 1 and 2 patients were not separately evaluated.

Although adult protocols for the management of early stage NLPHL have relied heavily on RT, pediatric and adolescent studies which typically include patients up to 21 years of age, have evaluated the use of chemotherapy alone as well as reduced dose RT in an effort to decrease secondary complications in a developing patient more prone to chronic toxicities. Low intensity chemotherapy, CVP (cyclophosphamide 500mg/m2, vinblastine 6mg/m2 D1/8, prednisolone 40mg/m2 PO D1-8) alone was evaluated in 45 patients with stage I/II NLPHL and 10 patients treated following relapse from surgery alone. For all patients the FFTF at 40 months was 75.4% and OS was 100%. In total, there were only 3 relapses, and no cases of aggressive lymphoma were observed but the median follow-up was only 41 months (54). The non-alkylator and non-bleomycin based

15

regimen VAMP (vinblastine, doxorubicin, methotrexate and prednisone) was evaluated in 110 children (median age 13.3 years, range 3.6-21 years) with stage I/II HL, including 33 patients with NLPHL (55). Patients in a CR by CT criteria received reduced dose IFRT (15 Gy) and those in a PR after 2 cycles received 25.5 Gy. With a median follow-up of 9.6 years the 10-year OS and EFS for the whole cohort were 96% and 89%, respectively. Remarkably, the actuarial 10year EFS for the NLPHL cohort was 100% compared to 85.4% for cHL (P=0.04). One thyroid cancer was reported within a RT field but otherwise normal fertility and organ function were noted. The Children’s Cancer Group (CCG) performed a phase III trial (CCG 5942) in HL patients using a variety of chemotherapy regimens depending on stage and the presence of risk factors (56). The hybrid regimen COPP (cyclophosphamide, vincristine, procarbazine and prednisone)/ABV was administered for 4 cycles if patients had low risk stage I or II disease. Patients in a CR by CT imaging were then randomized to receive no therapy or IFRT (20 Gy) whereas cases not in a CR all received IFRT. Within this study the outcome of 82 patients with NLPHL were reported separately, 66 (80.5%) of which had stage I/II disease without risk factors (57). Ultimately, 52 patients received chemotherapy alone and 29 received CMT. Although the outcomes included patients with all stages treated with other protocols/regimens, with a median follow-up of 7.7 years, the 5-year EFS and OS was 97% and 100%, respectively. Taken together, these studies support, that chemotherapy alone can achieve excellent outcomes in NLPHL in the pediatric/adolescent age group.

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Data supporting chemotherapy alone for the management of NLPHL is more limited in the adult population.

In the BCCA retrospective study, 14 patients

were treated with ABVD alone, employing a PET adapted approach in 11 of these cases. In the latter patients, if a CR was established on PET scan after two cycles of ABVD, two further cycles were given for a total of four cycles. There were no relapses or transformation events reported but the follow-up was short (51) ).

If chemotherapy is incorporated into the management of limited stage NLPHL, there has also been debate as to which multi-agent chemotherapy regimen is optimal in NLPHL. With evidence from advanced stage trials supporting that ABVD is superior to MOPP and less toxic, it is considered the standard chemotherapy for early stage cHL (58) but alkylator-based regimens have also been advocated for NLPHL (Table 3). The outcome of 37 patients with chemonaive NLPHL, including RT failures, that were enrolled in Cancer and Leukemia Group B (CALGB) trials (n=17) or treated at the Dana-Farber/Joint Center (n=20) were evaluated based on the type of chemotherapy utilized and an excess of failures in the ‘ABVD’ group was reported (59). However, only advanced stage patients were analyzed and it is unclear whether the pathology was re-reviewed for this analysis. Further, a subset of the 12 patients in the ‘ABVD’ group actually received the EVA regimen (etoposide, vinblastine, doxorubicin), which was previously shown to have high rates of relapse in cHL and the ‘alkylator’ group

17

included patients treated with MOPP or MOPP/ABVD, the latter having equivalent efficacy to ABVD alone (58).

Watchful waiting following surgical resection Watchful waiting has been evaluated in the pediatric population in an effort to reduce toxicities. Select patients with stage IA disease may remain free of progressive disease for long periods of time with this approach, but not surprisingly, the relapse rate is high. The largest pediatric series of watchful waiting comes from the European Network Group on Pediatric Hodgkin Lymphoma (EuroNet-PHL) with data collected on 58 pediatric cases treated with lymph node resection alone, 88% of which underwent complete resection and all but 2 patients had limited stage disease. At a median follow-up of 43 months, the overall PFS was 57% and one patient developed transformed aggressive NHL. The 5 y PFS was 67% for those in a CR after surgery compared to < 20% for those with incomplete resection (P=0.011). However, the OS was 100%, supporting that the salvage rate is excellent in these patients (60). In another prospective study from the Children’s Oncology Group, 52 patients with completely resected stage 1A disease were observed. With a median follow-up of 26 months, the 2-year EFS and OS were 80% and 100%, respectively (61). Longer follow-up will be necessary to determine the true relapse rate and risk of transformation but these results are encouraging that very select patients in whom toxicity is a concern may be able to avoid radiation and chemotherapy.

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One study of mostly adult patients (median age 30 years, range 8-69 years) included 58 patients who were observed following pathologic diagnosis (28). The 10-year PFS was only 41%, although neither the stage of this subgroup nor whether the tumour was completely excised was reported. A higher rate of transformation to secondary NHL in the watchful-waiting group was observed compared to those who received specific therapy (15.5% vs 7.4%, P=0.06) (28). The LYSA study included 114 patients with NLPHL who were initially observed, 104 of which had stage I or II disease. For the whole group, approximately half had relapsed by 5 years and for those undergoing complete resection, the median PFS was inferior to those that received initial therapy (82 months versus not reached, P<0.0356) (53). Anti-CD20 monoclonal antibodies The LP cells in NLPHL express high levels of CD20 antigen, thus the anti-CD20 monoclonal antibody rituximab has emerged as a potential treatment option for NLPHL. The Stanford group reported the mature results of phase 2 study of rituximab for newly diagnosed and previously treated patients with NLPHL. In the initial study, 4 weekly doses of rituximab were administered (limited course) to 22 patients but due to a high recurrence rate (41%) (62), the trial was modified to include a maintenance phase whereby rituximab was administered in similar fashion every 6 months for 2 years (extended course).

In the updated analysis,

in the previously untreated population (n=21), which included 14 patients with stage I or II disease, the ORR was 100%, CR 57%, but the 5 year PFS was only 41.7% and only marginally better considering the extended course patients

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separately (5 y 51.9%) (30). The study was too small to detail those with limited stage separately. Of concern in this small study, six patients (29%) developed transformation to aggressive NHL. In the GHSG study evaluating the outcome of stage IA NLPHL patients, 27 patients treated with a single course rituximab were included and the 4 y PFS was only 81.0% and inferior to those treated with RT or CMT although the 4 y OS was 100% (50). Summary Collectively, studies in limited stage NLPHL highlight the excellent outcome and the importance of toxicity considerations. Given the lack of randomized studies, treatment decisions should be guided by patient age, gender and in some cases preference.

Overall, watchful waiting and single agent rituximab are inferior

approaches leading to a high risk of relapse and it must be emphasized that this is a highly curable lymphoma. From the available evidence, stage 1A patients maybe effectively treated with either RT alone or CMT. The advantage of RT alone is lower risk of acute toxicity and shorter treatment course. However, higher RT doses and larger fields are required when used as a sole modality, which still may be relevant and impart a risk of secondary malignancies despite predominantly non-mediastinal involvement. Mature follow-up is still needed to evaluate the threshold of risk of RT used as a single modality and with CMT. Women with axillary node involvement may be at risk of breast cancer from axillary RT and pelvic radiotherapy may be an issue for women of child-bearing

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age. For both sexes, there may be a low but perceivable risk of sarcomas and RT to the supraclavicular region including the lung apex may place patients at risk of lung cancer. For those with stage IIA disease, CMT is preferable given that a lower dose of RT and a more restricted RT field can be applied as well as less data to support RT alone in this setting. This approach is endorsed by the ESMO guidelines although the NCCN guidelines suggest RT alone for both stage IA and IIA disease. The pediatric literature support excellent outcome using chemotherapy alone and emerging data in the adults suggest that this may be a viable option in younger adults with either stage I or stage II disease where long term secondary toxicities are a concern.

Management of Advanced stage NLPHL Approximately 20-25% of patients with NLPHL present with advanced stage disease. This typically includes patients with stage III or IV disease and depending on definition can also include stage II disease with risk factors such as bulky disease or B symptoms. Similar to issues described in the management of limited stage patients, the optimal chemotherapy is unknown. The ESMO guidelines support the use of either ABVD or escalated BEACOPP and the NCCN guidelines suggest ABVD CHOP and CVP with or without rituximab. As described, there has been some debate on whether an alkylator based chemotherapy may be superior in NLPHL, but there is no definitive evidence to

21

guide clinicians. Alkylator agents are known to increase the rates of subsequent myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In a series with a 13-year median follow-up of 88 NLPHL patients, 3 developed MDS; all of whom had received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone) as initial treatment (63). ABVD has not been associated with the development of MDS/AML or an increased risk of secondary malignancies when used alone (64). However, although usually not fatal, bleomycin can be associated with pneumonitis. The BCCA recently reported a matched control outcome analysis of 42 patients with advanced stage NLPHL compared to 82 with cHL (65) with mature follow-up of over 10 years. ABVD(like) chemotherapy was given to 86% of patients with NLPHL. Although the 10 year OS (NLPHL 83.5% vs cHL 81%) P=0.579) and 10 year HL FFTF (NLPHL 75% vs cHL 73%, P=0.610) were comparable, the TTP which also includes the development of secondary aggressive lymphoma as events was inferior in NLPHL (10 year 63% vs 73%, P=0.040). Further, the overall 10-year time to transformation in NLPHL was 15% and was 29% in those with splenic involvement at the time of diagnosis of NLPHL which was also reflected in an inferior TTP even if only ABVD treated patients are considered (10 year TTP 48% vs 71%, P=0.049) (63). Interestingly, in the ECOG phase 2 study evaluating rituximab in NLPHL, abdominal involvement was noted to occur at a higher frequency in those who subsequently developed transformation to aggressive lymphoma (30). There is very limited comparable data evaluating rituximab in combination with ABVD (R-ABVD). A French study reported the results of R-ABVD for the

22

management of NLPHL who had either advanced stage disease or due to location or tumor bulk, there was a preference to avoid RT(66). Half of the patients had advanced stage disease and dacarbazine was omitted in 10 patients due to intolerance and/or concern of exposure to alkylators. The 5 year lymphoma free survival was 80% but was inferior in advanced stage patients. Of interest, one patient who developed transformation to DLBCL had splenic involvement and B symptoms at diagnosis. With these findings, there may be a rationale for CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy in combination with rituximab (R-CHOP) as the preferred regimen over ABVD (or R-ABVD) given the higher risk of the development of secondary aggressive NHL, particularly in those with abdominal nodal or splenic involvement (65, 67).

The MDACC performed

a retrospective study of NLPHL patients in all stages, treated with a variety of approaches, including 15 patients treated with R-CHOP chemotherapy. With a median follow-up of 42 months, there have been no relapses or transformation events for the R-CHOP treated patients, the majority of whom had advanced stage disease (stage I/II n=4, stage III/IV, n= 11) (68). Although the follow-up is short, these results are encouraging and further study of R-CHOP in NLPHL is warranted.

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Management of Relapsed/Refractory NLPHL

For relapsed disease, a repeat biopsy is mandatory to confirm the diagnosis and exclude PTGC as well as the development of aggressive lymphoma. Compared to cHL, the number of first relapses is similar between NLPHL and cHL in the GHSG cohort (8.1% vs 8.0%; p=0.9242)(49); however, multiple relapses were observed in 27% of NLPHL (Diehl et al, 1999). The prognosis after relapse tends to be more favourable in NLPHL compared to cHL(69) (Diehl et al, 1999); however, this also reflects the dominant use of RT alone for primary therapy; therefore, salvage rates with chemotherapy would be expected to be higher in the relapsed setting. Treatment decisions at relapse depend on multiple factors, including age, initial treatment, duration of response, performance status, stage at relapse and underlying comorbidities. If RT alone was used in primary therapy, a CMT or chemotherapy alone may be favoured for limited stage disease, depending on disease site/extent.

Wirth et al. reported the outcome of 25 patients who

relapsed following RT(37), 22 of which received second line treatment, mostly with chemotherapy or CMT (n=17). For the whole group, 52% were free of second recurrence at 10 years and the estimated 10 year OS was 60% following first relapse. High dose chemotherapy and autologous stem cell transplant (HDC/ASCT) is used in most cases of relapsed/refractory cHL if chemotherapy was incorporated into the primary treatment (70). However, there have been very few studies as

24

well as conflicting data on this approach in NLPHL. In one study, HDC/ASCT was used in 8 relapsed patients with median failure free survival of 39.2 months and only 3 patients remaining in CR at 28-138 months post transplant (61). The MDACC reported on a series of 26 patients with relapsed/refractory NLPHL who underwent HDC/ASCT, 11 of which had rituximab with their conditioning regimen (71). Eight had biopsy proven transformation to large cell lymphoma. The 5 year EFS and OS were 69% and 76%, respectively. A more recent study evaluated the outcome of 17 patients with relapsed/refractory NLPHL who received HDC/ASCT between 1996-2014 (72). This analysis did include a few pediatric/adolescent patients (median age 22 y, range 10-54 y) and 4 patients with transformed disease. For those that received R-ESHAP the outcome was superior compared to those that received ESHAP alone (5 year EFS 100% vs 56%, P=0.041). These results suggest that for selected patients, HDC/ASCT represents a viable option for patients with relapsed/refractory NLPHL, including those with transformed disease.

Single agent rituximab has been successfully used in patients with relapsed/refractory disease. The ORR is 94% and median TTP 33 months in relapsed patients using a standard course of rituximab (73). The ECOG study reported a 5 year PFS rate of 36.4% and 71.4% in the limited and extended course rituximab groups, respectively. Combination of rituximab and chemotherapy was also shown to be effective in this setting (63).

25

Conclusions

The management of NLPHL is less well defined than for cHL and differs in the pediatric and adult populations, however, lessons can be learned from studies in both age groups. For stage I disease, RT alone and CMT are both effective options; however, it is unknown whether lower doses of RT can be used in the absence of chemotherapy. In cases with completely resected disease and where treatment toxicity is of concern, watchful waiting may be an option in carefully selected patients. For stage II disease, incorporating chemotherapy, in the form of ABVD, may be preferred with some studies suggesting an excess of relapse with RT alone. This approach is endorsed by the ESMO guidelines. The pediatric literature supports excellent outcomes using chemotherapy alone in limited stage patients and this approach should be further explored in adults. For advanced stage disease various chemotherapy regimens are endorsed. Currently, ABVD remains the standard regimen; however, R-CHOP should be strongly considered in the presence of splenic and/or abdominal nodal involvement. As a potentially curable lymphoma, the optimal treatment strategy should aim to minimize the risk of relapse and secondary aggressive lymphoma whilst reducing the risk of long-term toxicity in this young population.

26

Figure 1. Histopathologic growth pattern of NLPHL according to Fan et al. A) B cell rich nodular pattern (pattern A), B) pattern B: serpiginous/interconnected; C) pattern C, which is characterized by prominent extranodular LP cells; D) T cell rich nodular pattern (pattern D); E) diffuse T cell/histiocyte rich B cell lymphoma-like pattern (pattern E); F) diffuse moth eaten pattern (pattern F). All cases are stained with an antibody recognizing CD20, original magnification x100, scale bars equal 100m.

27

28

Figure

2.

Characteristic

histopathologic

features

of

NLPHL

and

transformed disease A) typical LP cells with multilobated nuclei in a background of small lymphocytes; B) LP cell characteristically surrounded by T cells with follicular T helper cell phenotype (CD57 staining); C) typical nodular growth pattern with predominance of small B lymphocytes and numerous tumour cells (CD20 staining); D) meshwork of CD21-positive follicular dendritic cells within the B cell nodules; E) transformed NLPHL with a T cell/histiocyte rich B cell lymphoma-like pattern in the spleen; F) same case as seen in (E), tumour cells are highlighted with CD20 whereas the background is mainly composed of T cells and histiocytes, original magnification C) and D) x100, F) x200, A), B) and E) x400, scale bars equal 100m (C, D and F) or 50m (A, B, E).

29

30

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Malignant cells Morphology Reactive background

Immunophenotype

Transcription factors EBER

NLPHL LP cells Nodular, nodular and diffuse Mostly small B cells, CD4+CD57+PD1+ T cell rosettes CD20+, CD21+, CD79a+, CD75+, a BCL6+, EMA+/- , J chain+/-, sIg+/-, CD15-, b CD30PU.1+/-, PAX5+, OCT2+, BOB.1+ d Absent

cHL HRS cells Diffuse, interfollicular, nodular Lymphocytes, histiocytes, eosinophils, plasma cells T-cells > B-cells CD20-/+, CD21+/- (varies by b subtype), CD45-, CD79a-/+ , EMA-, J chain-, CD15+/-, CD30+ c

PU.1-, PAX5+ , OCT-2-/+, BOB.1-, Varies depending on subtype, about 50%

TCRBCL Scattered large B cells Diffuse, vaguely nodular Mostly small CD8+ T cells, CD68+ histiocytes CD20+, CD21-, CD45+, CD79a+, CD75+, BCL6+, EMA+/-, J chain+/-, sIg+/b CD15-, CD30PU.1-/+, PAX5+, OCT2+, BOB.1+ Rare

Table 1: Histologic and immunophenotypic comparison of NLPHL, cHL and TCRBCL + all cases positive, +/- majority of cases positive, -/+ minority of cases positive, - all cases negative NLPHL=nodular lymphocyte predominant Hodgkin lymphoma; cHL = classical Hodgkin lymphoma; TCRBCL=T-cell rich B-cell lymphoma a EMA positive in 50% b Positive in rare cases c Up to 10% may be negative d EBER rarely expressed in NLPHL and does not preclude the diagnosis

45

Median age (y) Male sex (%) Stage III-IV (%) B symptoms (%) a Mediastinal involvement (%) Extranodal (%) ≥3 nodal areas

NLPHL (GHSG, n=394)

cHL (GHSG, n=7904)

TCRBCL (n=61)

37 75 21 9 31 6 28

33 56 39 40 55 14 55

30 71 65 46 32 61 --

Table 2: Comparison of clinical features of NLPHL, cHL and TCRBCL NLPHL=nodular lymphocyte predominant Hodgkin lymphoma; cHL = classical Hodgkin lymphoma; TCRBCL=T-cell rich B-cell lymphoma a Mediastinal involvement in ETFL study was only 7% (Diehl et al, 1999)

46

ESMO treatment guidelines Stage IA without risk factors Other stages

Relapsed disease

30 Gy IFRT alone Treat identically to CHL a Limited : 2 cycles of ABVD + 20 Gy IFRT a Intermediate : 4 cycles of ABVD + 30 Gy IFRT or 2 cycles of escBEACOPP + 2 cycles of ABVD (< 60 y) + IFRT (30Gy) or ISRT a Advanced : 6-8 cycles of ABVD or 8 cycles of escBEACOPP(<60 y) Obtain biopsy Localized relapse can be treated with rituximab alone Advanced relapse should be treated with aggressive regimen +/rituximab

NCCN treatment guidelines Stage IA, IIA (non-bulky) Bulky IA , IIA Stages IB, IIB Stages IIIA, IVA

Stage IIIB, IVB

Observe (if 1A and complete excision) ISRT (30-36Gy)(preferred) b Chemotherapy + ISRT +/- Rituximab Chemotherapy +/- Rituximab +/- ISRT Rituximab +/- ISRT Local RT (palliation) Rituximab Chemotherapy +/- Rituximab +/- ISRT

Table 3: Proposed ESMO and NCCN treatment guidelines for NLPHL a

Limited: stage I-II without risk factors Intermediate: stage I, IIA with ≥ 1 risk factors; stage IIB with elevated ESR or ≥ nodal areas Advanced: Stage IIB with large mediastinal mass or extranodal disease, stages III/IV b Chemotherapy options include: ABVD, CHOP, CVP Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; BEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP = cyclophosphamide, vincristine, and prednisone; IFRT = involved field radiotherapy; ISRT = involved site RT

47

Study (Total N)

Limited stage n

Patholog y review

LYSA Lazarovici 2015

259 stage I/IIA

85%

256 (100%) stage 1A

71 (87%) stages I-IV

Adult Eichenauer 2015

Pediatric Appel 2012a

Media n age y (range ) 38 (1879)

Treatmen t (% of total)

Media n follow -up (y)

Time to Even t

OS

2° aggressiv e NHL

RT (24%) CMT q (13%) CHT (14%)

4.7 (<1m36 y)

Not specifie d by treatme nt or stage

7.6% (All stages)

Yes (clinical trial)

39 y

EFRT (19%) IFRT(30G y) (42%) CMT (28%)

7.6

8y OS 95.7% 8y OS 99.0% 8y OS 98.6%

1.9%

Yes (69.5% central review)

≤ 21

CHT 63%

a

7.7

CMT 35%

a

7.7

5y PFS  q 80% 5y PFS  80% 5y PFS  80% 8y PFS 84.3 % 8y PFS 91.9 % 8y PFS 88.5 % 5y b EFS 96% 5y b EFS 100% 3.3y FFTF 75.4 %

Pediatric Shankar 2012

45 (100%) stages I-II

Yes

13 (4-17)

CVP 100%

3.4

Adult Savage 2011

88 (100%) stages IA/IB/IIA

Yes

36.5

RT 40%

18.6

CHT, d CMT 58%

5.7

Pediatric/ad ult Farrell 2011

56 (81%) stages I-II

Yes

39 (1179)

RT 54%

4.4

Pediatric/ad ult Chen 2010

113 (100%) stages I-II

Yes

27 (3-77)

RT 82% e CMT 12%

11.3

CHT 6%

e

11.3

RT 27% f CHT 9% f CMT 29%

9.5

Pediatric/ad ult Biasoli 2010

136 (83%) stages I-III

Yes

30 (8-69)

5y 100%

b

0%

5y 100%

b

0%

3.3y 100%

0%

10 y PFS 66.5 % 10y PFS 93% 5y RFS 94%

10y 85%

5.7%

10y 93%

0%

5y 100%

2.9%

10y b PFS IFRT 64% RRT 85% EFR T 81% 10y PFS 14% 10y b PFS 66%

10y IFRT 100% RRT 96% EFRT 95%

b

NA

10y 83%

NA

b

10y 93%

c

7.4%

48

Adult Nogova 2008

Pediatric/ad ult Chera 2007 Pediatric Hall 2007

Adult Nogova 2005

b

NA

4.2y 96%

b

NA

10y 85%

b

0%

10y RFS 77% 10y b RFS 90% 2y FFTF 100% EFR T 92% IFRT 2y FFTF 97% 15y FFP 82%

10y 100%

0%

248 (63% early h favourable) stages IA/IIA 63 (16% early unfavourable h ) stages IA/IB/IIA 32 (94%) stages I-III

Yes

37

RT or g CMT

4.2

4.2y FFTF 93%

4.2y 96%

Yes

37

CMT

g

4.2

4.2y FFTF 87%

No

24 (5-70)

RT 80% i CMT 20%

12.3

10y b RFS 81%

35 (83%) stages I-IV

Yes

10 (3-15)

IFRT 52% (stage IA)

8.9

ChlVPP 48%

8.9

EFRT 34% IFRT 34%

6.5 EF 1.4 IF

ABVD + IFRT/EFR T 31% RT

3.3

k

131 (100%) stage IA

j

Yes

39 (1673)

0%

2y 100%

0%

2y 100%

0%

15y 83%

4.4%

Pediatric/ad ult Wirth 2005

202 (100%) stages I-II

No

31 (2-79)

Adult Feugier 2004

42 (100%) stages IA/IIA

Yes

NA (1865)

CMT

NA

15y FFP 92%

15y 86%

2%

Adult Wilder 2002

48 (100%) stages IA/IB/IIA

Yes

28 (1649)

RT 77%

9.3

10y RFS 77% 10y RFS 68% 8y FFTF stage I 85%, stage II 71% 10y b RFS 80%

10y 90%

0%

10y 100%

0%

8y Hodgkin specific survival stage I 99% stage II 94% b 10y 93%

0.9% n deaths

10y b FFP 45%

10y 71%

l

15

b

10y 95%

CMT 23%

9.3

Adult Diehl 1999

175 (80%) stages I-II

Yes

35

99% stage I 95% & stage II: RT or m CMT

6.8y

Pediatric/ad ult Bodis 1997

66 (88%) stages I-IV

Yes

NA

RT 86% CHT 8% o CMT 6%

10.8

Adult Orlandi 1997

51 (75%) stages I-IV

Yes

35 (1486)

RT 38% CHT 34% p CMT 28%

6.3

b

0%

7.4%

49

Table 4: Studies evaluating radiotherapy, combined modality therapy and chemotherapy alone in primarily limited Stage NLPHL

a

CHT includes IFRT and COPP/ABV n=80 or 2 cycles of COPP/ABV, 2 cycles of high-dose cytarabine with etoposide, and two cycles of cyclophosphamide, vincristine, doxorubicin, methylprednisolone, and prednisone n=2 b Combined outcome for limited and advanced stage patients c Transformation was seen in RT treated patients only d Chemotherapy in CHT and CMT includes ABVD n=46, MOPP/ABV n=4, MOPP n=1 e CMT includes radiation + MOPP n=3, ABVD n=5, and vinbastine, doxorubicin methotrexate and prednisone (n=5); CHT includes ABVD n=2, MOPP n=2, chlorambucil and vinblastine n=1, mechlorethamine, vincristine, doxorubicin and bleomycin n=2 f Chemotherapy in CHT and CMT groups included MOPP-like chemotherapy either alone or combined with ABV for 50% of patients and ABVD for other 50% g Staging defined by ESMO (see table 3) h Early favourable : EF or IF, ABVD + EF/IF; early unfavourable: COPP/ABV/IMEP +EFRT, COPP/ABVD+EFRT, ABVD+IFRT, BEACOPP+IFRT i Chemotherapy included ABVD n=1, MOPP and ABVD n=2, DBVE n=3, BCVPP n=1 j Patients also included in Nogova 2008 study k CMT includes EFRT + ABVD n=30, EBVM n=10, 7 drug CT (Epirubicin, bleomycin, vinblastine, vincristine, cyclophosphamide, etoposide, methotrexate, methylprednisolone) n=2 l CM includes MOPP n= 6, NOVP n=5 m Chemotherapy was MOPP-, ABVD- or MOPPABVD-like in 94% n Total NHL was not reported, but 2 deaths (0.9%) resulted from NHL out of 219 patients o Chemotherapy in CHT and CMT groups included MOPP, ABVD, MOPP/ABV, ChlVPP, EVA p Chemotherapy in CHT and CMT groups included MOPP n=14, ABVD n=16 or alternating MOPP/ABVD n=12 q CHT included ABVD(like), BEACOPP, CHOP, ACVBP, MINE, DHAP, ICE, CVP, chemo-immunotherapy. 63 patients received RT (62 stage I/II); 68 received CMT (36 stage I/II); 40 received CMT (33 stage I/II) PFS estimated from published survival curves

Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; BCVPP = carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone; BEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; ChlVPP = chlorambucil, vinblastine, procarbazine, and prednisolone; CHT = chemotherapy; CMT = combined modality therapy; COPP = cyclophosphamide, vincristine, procarbazine, and prednisone; CVP = cyclophosphamide, vincristine, and prednisone; DBVE = doxorubicin, bleomycin, vincristine, and etoposide; EFRT = extended field radiotherapy; EFS = event free survival; EVA = etoposide, vinblastine, and doxorubicin; FFP = freedom from progression; FFTF = freedrom from treatment failure; IMEP = ifosfamide, methotrexate, etoposide, and prednisone; IFRT = involved field radiotherapy; MOPP = mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone; NA = not reported/not available; OBS=Observation; OS = overall survival; PFS = progression free survival; RFS = relapse free survival; RRT = regional radiotherapy; RT = radiotherapy; y (years)

50

Study

N

Pathology review

Median age y (range) 38 (18-79)

Median follow-up (y) 4.7 y

Time to Event

OS

2° NHL

Adult Lazarovici (2015) Pediatric Appel 2012b

114 stage I/2 (91%) stage IA

85%

5 y PFS  50%

Not reported

Not reported

Yes

≤ 21

2.2

2y EFS 80.3%

2y 100%

0%

Pediatric/adult Biasoli 2010

58 (35%) stages I-II

Yes

30 (8-69)

9.5

10y PFS 41%

10y 91%

15.5%

Pediatric Mauz-Korholz 2007

58 (100%) stages I-III

Some (55/58)

11 (4-17)

3.6

4.2y PFS 57%

4.2y 100%

0%

Table 5: Studies of watchful waiting in NLPHL

51

Study (Total N)

Advanced stage (%)

Pathology review

Xing 2012 Fanale 2010

42 stages III-IV 12 (60%) stages I-IV

Canellos 2010

37 (100%) stages III-IV

Nogova 2008 Diehl 1999

83 (21%) stages IIBIV 44 (20%) stages III-IV

Treatment (% of total)

Yes

Median age y (range) 37

Yes

40

CHOP-R +/IFRT

3.5

NA

NA

ABVD or EVA 32% MOPP+/ABVD 68% b CMT

81% stage III & 95% stage IV: c CHT or CMT

Yes

37

Yes

35

ABVD (83%)

Median follow-up (y) 10

Time to Event

OS

2° NHL

10y FFTF 76% a 5y PFS 95%

10y 86%

19%

5y 95%

a

0%

NA

‘Failure’ 75%

NA

NA

NA

‘Failure’ 32%

NA

NA

4.2

4.2y FFTF 77%

All stages 96%

NA

6.8

8y FFTF stage III 62% stage IV 24%

8y Hodgkin specific survival: Stage III 94% Stage IV 41%

0.9%

Table 6: Studies of Primarily Advanced Stage NLPHL a

Combined outcome for limited and advanced stage patients CMT includes radiotherapy and COPP/ABV/IMEP, COPP/ABVD, or BEACOPP c Chemotherapy was MOPP-, ABVD- or MOPPABVD-like in 94% d Total NHL was not reported, but 2 deaths (0.9%) resulted from NHL out of 219 patients b

Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; BEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; CHOP-R = cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab; CHT = chemotherapy; CMT = combined modality therapy; COPP = cyclophosphamide, vincristine, procarbazine, and prednisone; EVA = etoposide, vinblastine, and doxorubicin; FFTF = freedrom from treatment failure; IMEP = ifosfamide, methotrexate, etoposide, and prednisone; IFRT = involved field radiotherapy; MOPP = mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone; NA = not reported/not available; OS = overall survival; PFS = progression free survival; RT = radiotherapy; y (years)

52

d