From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

2014 123: 3567-3573 doi:10.1182/blood-2013-12-541078 originally published online April 8, 2014

Advanced-stage nodular lymphocyte predominant Hodgkin compared with classical Hodgkin lymphoma: a matched pair outcome analysis

Katharine H. Xing, Joseph M. Connors, Anky Lai, Mubarak Al-Mansour, Laurie H. Sehn, Diego Villa, Richard Klasa, Tamara Shenkier, Randy D. Gascoyne, Brian Skinnider and Kerry J. Savage

Updated information and services can be found at: http://bloodjournal.hematologylibrary.org/content/123/23/3567.full.html Articles on similar topics can be found in the following Blood collections Clinical Trials and Observations (3892 articles) Free Research Articles (2531 articles) Lymphoid Neoplasia (1767 articles)

Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests

Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints

Information about subscriptions and ASH membership may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.

From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only. Regular Article

CLINICAL TRIALS AND OBSERVATIONS Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis

Katharine H. Xing,1 Joseph M. Connors,1 Anky Lai,2 Mubarak Al-Mansour,3 Laurie H. Sehn,1 Diego Villa,1 Richard Klasa,1 Tamara Shenkier,1 Randy D. Gascoyne,4 Brian Skinnider,4 and Kerry J. Savage1

1Centre for Lymphoid Cancer and Department of Medical Oncology, British Columbia Cancer Agency and the University of British Columbia, Vancouver, BC, Canada; 2Cancer Surveillance and Outcomes, Population Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada; 3Oncology Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia; and 4Centre for Lymphoid Cancer and Department of Pathology, British Columbia Cancer Agency, Vancouver, BC, Canada

Key Points Due to disease rarity, there is limited information regarding the optimal therapy and outcome for patients with advanced-stage nodular lymphocyte-predominant Hodgkin • TTP is inferior in patients with lymphoma (NLPHL). Forty-two patients with NLPHL by the Revised European-American advanced-stage NLPHL Lymphoma/World Health Organization classification with advanced-stage disease were compared with CHL. identified and paired 1:2 with a matched control with classical Hodgkin lymphoma (CHL) • Spleen involvement is matched by age, gender, stage, decade of diagnosis, and treatment received. The median associated with an increased follow-up was 11.3 years (range, 1.9 to 35.5 years) for NLPHL patients and 10.7 years (range, risk of secondary aggressive 1.6 to 26.3 years) for CHL patients. The majority received , bleomycin, vinblastine, and dacarbazine (ABVD)–like chemotherapy. Although the 10-year overall lymphoma in patients treated survival (OS) (P 5 .579) and HL freedom from treatment failure (HL-FFTF) were similar with ABVD-like chemotherapy. between NLPHL and CHL patients (75% vs 73%; P 5 .610), the time to progression (TTP), which also includes the development of secondary , was inferior in NLPHL (10-year, 63% vs 73%; P 5 .040). Splenic involvement was associated with an inferior 10-year TTP in patients treated with ABVD (48% vs 71%; P 5 .049) and an increased cumulative incidence of secondary aggressive lymphoma (P 5 .014) providing a rationale for further evaluation of cyclophosphamide, doxorubicin, , and prednisone (CHOP) with rituximab in NLPHL. (Blood. 2014;123(23):3567-3573) Introduction

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is secondary aggressive non-HL (NHL), most commonly diffuse large a rare Hodgkin lymphoma (HL) subtype, representing only 5% of all B-cell lymphoma (DLBCL), has been noted to occur at a higher cases.1 It is distinguished from classical HL (CHL) by the presence of frequency in NLPHL.3-6 Whether this represents a true transformation large malignant cells known as lymphocyte-predominant (LP) cells, from underlying NLPHL is a matter of debate. It may be the result of sometimes referred to as “popcorn” cells because of their lobulated a common precursor cell or it may be the result of concurrent NLPHL appearance. In contrast to the Hodgkin-Reed-Sternberg (HRS) cells and DLBCL at the time of diagnosis. There has been a wide range of of CHL, the LP cells retain a B-cell phenotype with expression of rates of transformation reported across studies (0.9% to 14%)1,3-5 CD20 and CD79a. The large retrospective review performed by the which may reflect multiple factors, including a lack of biopsy at disease European Task Force on Lymphoma (ETFL) demonstrated that expert relapse, variable risk profiles, absence of expert pathology review, review by an experienced hematopathologist that incorporates both and short follow-up in some studies, especially because this event morphologic and immunophenotypic criteria is mandatory for the has been reported to occur up to 20 years after diagnosis.4 diagnosis of NLPHL.2 In this comprehensive analysis, just over Given the rarity of this disease, there is limited information half of the submitted cases were confirmed to be NLPHL, which regarding the optimal management of NLPHL, and this is parti- brings into question the validity of older studies before the availability cularly evident for advanced-stage disease. At the British Colum- of immunophenotyping. bia Cancer Agency (BCCA), patients with HL of all types are Clinically, patients with NLPHL typically present with limited- similarly treated. Thus, the purpose of this study was to evaluate stage disease with involvement of peripheral node sites, and only the outcome of patients with advanced-stage NLPHL compared 20% present with advanced-stage NLPHL at diagnosis. Unlike CHL, with a cohort of matched historical controls with CHL to highlight there is a tendency for multiple and late relapses. Furthermore, the distinct natural history of this rare HL subtype.

Submitted December 6, 2013; accepted March 25, 2014. Prepublished online The publication costs of this article were defrayed in part by page charge as Blood First Edition paper, April 8, 2014; DOI 10.1182/blood-2013-12- payment. Therefore, and solely to indicate this fact, this article is hereby 541078. marked “advertisement” in accordance with 18 USC section 1734. © 2014 by The American Society of Hematology

BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23 3567 From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

3568 XING et al BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23

Table 1. Baseline characteristics of patients with advanced-stage NLPHL and matched controls with advanced-stage CHL Patients and methods NLPHL (n 5 42) CHL (n 5 84)* The BCCA Lymphoid Cancer database was searched to identify all patients Characteristic No. % No. % $ age 12 years with advanced-stage NLPHL (stage III or IV disease or stage II Follow-up, years with B symptoms and/or bulky disease) who were diagnosed between 1970 Median 11.3 10.7 and 2011. Patients diagnosed before the routine use immunophenotyping Range 1.9-35.5 1.6-26.3 used in the Revised European-American Lymphoma/World Health Organi- Male sex 30 71 58 69 fi 7 zation classi cation were subjected to pathologic re-review by an expert Age, years BCCA hematopathologist (B.S.). The remaining cases had previously been Median 37 37 centrally reviewed at the BCCA. Range 12-75 12-78 Clinical information was collected at the time of the diagnosis of NLPHL, $45 17 40.5 31 37 including splenic involvement identified either by splenectomy at the time of Stage staging laparotomy or by computed tomography (CT) imaging in the more II 25 45 modern treatment era (defined as splenic nodules or splenomegaly that III 37 90 76 90 resolves posttreatment). None of the patients had a staging positron emission IV 25 45 tomography scan. In addition to standard doxorubicin, bleomycin, vinblastine, PS $2 4 9.5 8 9.5 and dacarbazine (ABVD) chemotherapy, other anthracycline-based treatment B symptoms 9 21 18 21 regimens included mechlorethamine, vincristine, procarbazine, and prednisone/ Extranodal disease 2 5 8 9.5 doxorubicin, bleomycin, and vinblastine (MOPP/ABV); vincristine, doxoru- Spleen involvement 14 33 33 39 bicin, bleomycin, etoposide, and prednisone (ODBEP); and vinblastine, Bulky mass $10 cm 0 0 etoposide, cyclophosphamide, doxorubicin, bleomycin, vincristine, and Mass $5cm 13313845 prednisone (VECABOP), all of which were considered to be ABVD-like IPS $4056 8,9 and have been previously shown to have equivalent efficacy. Prior to Elevated LDH 3 7 16 19 1980, patients received MOPP chemotherapy or extended field radio- Treatment therapy (RT). ABVD-(like) chemotherapy 36 86 74 88 For each patient with NLPHL, two matched controls diagnosed with MOPP 6 radiation 4 9.5 6 7 CHL were identified with blinding for outcome and matching by age (12-30, Radiation alone 2 5 4 5 31-45, 46-60, .60 years), gender, stage, decade of diagnosis (1970-1980, 5 5 1981-1990, 1991-2000, 2001-present), and chemotherapy received. This There were missing values for mass size: NLPHL n 3, CHL n 4; spleen involvement: NLPHL n 5 1; PS: NLPHL n 5 1, CHL n 5 2; elevated LDH: NLPHL study was approved by the Research Ethics Board at the BCCA. n 5 7, CHL n 5 18; IPS score: NLPHL n 5 5; CHL n 5 11. IPS, International Prognostic Score; LDH, lactate dehydrogenase. *Matching was performed for 42 NLPHL patients. Statistical analysis

HL freedom from treatment failure (HL-FFTF) was measured from the date of pathologic diagnosis of HL to the date of relapse and/or progression or death 2 had NHL; 1 elderly patient did not receive any therapy and was lost as a result of HL or acute treatment toxicity. Time to progression (TTP) was measured from the date of diagnosis to the date of relapse and/or progression to follow-up; and 10 older patients for whom pathologic re-review fi or death as a result of any lymphoma (including HL or development of was not possible because paraf n-embedded tissue was not available a secondary NHL) or death as a result of acute treatment toxicity.10 Overall for immunophenotyping. For each of the 42 remaining patients with survival (OS) was measured from the date of diagnosis to the date of last NLPHL, two matched CHL controls were identified as described follow-up or death from any cause. By using a competing risk analysis, the above. cumulative incidence of secondary aggressive NHL (time to transformation) For the NLPHL patients, the median age was 37 years (range, was calculated from the date of diagnosis of NLPHL to the date of trans- 12 to 75 years) and the majority were male (71%) with a good formation to aggressive lymphoma in which deaths as a result of unrelated performance status (PS #1; 90%). All had low-risk disease by the causes were treated as competing events. Baseline characteristics were IPS (Table 1).12 Most patients had stage III disease (90%), and B compared by using the x2 test. The Kaplan-Meier method was used to symptoms were present in only 9 patients (21%). The median mass calculate survival and comparisons were made by using the log-rank test.11 All statistical analyses were performed by using SPSS, versions 11 size was 4 cm (range, 1 to 9 cm), and none of the patients had bulky $ and 14 (SPSS, Chicago, IL), and the cmprsk package of R software, disease (mass 10 cm). Spleen involvement was present in 14 version 2.14.2., was used for the competing risk analysis using Gray’s patients (33%): 5 identified by splenectomy at the time of staging test. laparotomy, 8 by CT imaging (7 splenic nodules, 1 splenomegaly), and 1 through documentation in the clinical notes. Most patients received standard ABVD (n 5 27;64%)orABVDequivalent (ABVD-like) chemotherapy (MOPP-ABVD, n 5 1; MOPP/ABV, n 5 5; ODBEP, n 5 18; VECABOP, n 5 213) (total ABVD-like, Results n 5 36; 85%), none of whom received consolidation RT. A 5 Baseline characteristics and primary therapy of patients minority received MOPP alone (n 4) with or without RT and two with advanced-stage NLPHL vs matched controls with patients diagnosed in the earliest treatment era were treated with fi advanced-stage CHL extended eld RT alone. For the matched control analysis, 84 patients with CHL were In total, 72 patients with advanced-stage NLPHL were identified, of identified, most of whom had nodular sclerosis CHL (n 5 67; 80%), whom 30 were excluded: 11 had concurrent DLBCL at diagnosis and the remaining patients had mixed cellularity (n 5 9), lymphocyte- (composite, n 5 7; discordant, n 5 3) or were identified as a having rich (n 5 2), lymphocyte-depleted (n 5 1), or CHL not otherwise a gray-zone lymphoma (n 5 1); 6 had CHL (2 lymphocyte rich, 1 specified (n 5 5) subtypes. Eight of 84 matched controls deviated from mixed cellularity, 1 lymphocyte depleted, 2 not otherwise specified); the matching schema: 1 control received MOPP/ABVD instead of From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23 SURVIVAL OF ADVANCED-STAGE NLPHL 3569

Figure 1. HL-FFTF in NLPHL vs CHL.

the MOPP chemotherapy that the NLPHL patient received, 5 were Risk factors for transformation and recurrent NLPHL in identified in the preceding (n 5 2) or following (n 5 3) decade, and 2 advanced-stage NLPHL were from the next age group. The groups were equivalent for the matched baseline characteristics. Similarly, for unmatched character- Among the 42 patients with NLPHL, 21 relapsed following initial istics, there were no differences between the groups (PS P 5 1.000, B therapy: 14 with NLPHL and 7 with aggressive NHL. One patient fi symptoms P 5 1.000, IPS $4 P 5 .259, elevated LDH P 5 .259, with pathologically con rmed NLPHL was clinically suspected to extranodal involvement P 5 .351, mass size $5cmP 5 .124, and have aggressive NHL on the basis of clinical presentation (rapidly spleen involvement P 5 .608). Spleen involvement was doc- enlarging 20-cm abdominal mass, LDH 5 times the upper limit of umented in 33 patients with CHL, 9 by splenectomy at the time of normal). staging laparotomy and the remainder on CT imaging (22 had splenic By using a competing risk analysis, spleen involvement at the fi nodules, 2 had splenomegaly). time of diagnosis of NLPHL was associated with a signi cantly increased cumulative incidence of transformation (10-year cumula- tive incidence, 29% vs 7.8%; P 5 .019; Table 4). Similarly, con- Outcome analysis: NLPHL vs matched CHL controls sidering only the patients who received ABVD-like treatment, the The median follow-up for NLPHL and CHL patients was 11.3 years cumulative incidence of transformation at 10 years was 34% in the (range, 1.9 to 35.5 years) and 10.7 years (range, 1.6 to 26.3), spleen-positive group compared with 9% in the spleen-negative P 5 fl respectively. The 10-year HL-FFTF, which reflects only relapses from group ( .014). This was also re ected in an inferior TTP in patients HL, was similar between patients with NLPHL or CHL (75% vs 73%, with splenic involvement treated with ABVD-like regimens (10-year P 5 respectively; P 5 .610) (Figure 1; Table 2). However, late relapses of TTP, 48% vs 71%; .049, Figure 4). Interestingly, if only patients $5 years were more common in patients with NLPHL than in those without spleen involvement are considered, the TTP is similar in with CHL (21% [n 5 9] vs 2.4% [n 5 2]; P 5 .001), representing 45% patients with CHL and NLPHL who received ABVD-like treatment P 5 and 10% of all relapses, respectively, and a plateau in the HL-FFTF (10-year TTP, 74% vs 71%; .840). $ curve is not apparent in NLPHL (Figure 1). Transformation to an A large tumor mass ( 5 cm) at initial presentation was also fi P 5 aggressive NHL occurred exclusively in NLPHL (Table 2). By using identi ed as a risk factor for transformation ( .011), and the a competing risk analysis, the cumulative risk of transformation at 15 presence of B symptoms was associated with an inferior OS (Table 4). years was 24%.There was a trend to a worse OS in ever-transformed vs never-transformed patients (10-year OS, 92% vs 56%; P 5 .173). The median time to transformation in NLPHL patients was 5.45 years Table 2. Outcome of patients with advanced-stage NLPHL (range, 0.3 to 20.3 years). This also translated into an inferior TTP compared with matched controls with advanced-stage CHL (P 5 .040) (Figure 2; Table 2) in patients with NLPHL compared to Survival (%) those with CHL, which encompasses relapses from both HL and HL subtype 5-Year 10-Year 15-Year P aggressive NHL. Similar results were obtained if the TTP analysis was HL-FFTF NLPHL 82 75 52 .610 confined to only patients with NLPHL and CHL receiving ABVD- CHL 78 73 73 like chemotherapy (P 5 .041). TTP NLPHL 72 63 44 .040 The OS was similar between patients with NLPHL and those with CHL 78 73 73 CHL (P 5 .826) (Figure 3; Table 2), but deaths as a result of HL were OS NLPHL 89 83.5 74 .826 the predominant cause of mortality in the CHL group (47%) whereas CHL 91 81 68 for patients in the NLPHL group, deaths as a result of secondary TTT NLPHL 12 15 24 .00018 aggressive NHL were a common cause of mortality (40%) (Table 3) CHL 0 0 0 (P 5 .021). TTT, time to transformation. From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

3570 XING et al BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23

Figure 2. TTP in NLPHL vs CHL.

Poor PS was associated with an inferior HL-FFTF and OS, and a trend (R-CVP) chemotherapy, rituximab alone, or lomustine. Eight was observed for TTP; however, this finding was present in only patients subsequently relapsed with NLPHL, one of whom had a small group of patients (Table 1). Male gender was associated with a third relapse of aggressive NHL 7 years after the initial diag- an inferior HL-FFTF, and a trend toward an inferior HL-FFTF was nosis; thus, overall, almost 60% of patients had a subsequent observed in patients receiving therapy that did not include ABVD-like lymphoma relapse. chemotherapy (10-year HL-FFTF, 78.5% vs 67%; P 5 .147) (Table 4). Nine patients ultimately developed a secondary aggressive NHL, 4 of whom the pathology showed DLBCL, 2 resembled T-cell/ Therapy for relapsed NLPHL and secondary aggressive NHL histiocyte-rich large B-cell lymphoma (THRLBCL-like), and 1 case showed DLBCL with areas resembling THRLBCL and a subsequent Of the 14 patients with relapsed NLPHL, 7 had advanced-stage relapse was consistent with THRLBCL-like histology. In one patient, disease, 6 had limited-stage disease, and 1 had unknown disease a fine-needle aspirate demonstrated aggressive NHL; however, full status. As described, 1 patient was treated as having aggressive subclassification was not possible because of limited pathologic ma- lymphoma because of a suggestive clinical presentation. For the terial, and the remaining patient was presumed to have transformed remaining 13 patients, therapy was heterogeneous: 4 patients re- disease, given an aggressive course as described above. In this group, 3 ceived second-line chemotherapy with gemcitabine, dexameth- patients received high-dose chemotherapy and autologous stem cell asone, and cisplatin (GDP) (n 5 3) or MOPP (n 5 1) followed transplant and 5 patients received cyclophosphamide, doxorubicin, by high-dose chemotherapy and autologous stem cell transplant; vincristine, and prednisone (CHOP) –like chemotherapy with (n 5 4) 4 received ABVD-like chemotherapy; 2 received RT alone; and 1 each or without (n 5 1) rituximab and with etoposide substitution if the received rituximab, cyclophosphamide, vincristine, and prednisolone anthracycline maximal dose was reached. One patient received palliative

Figure 3. OS in NLPHL vs CHL. From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23 SURVIVAL OF ADVANCED-STAGE NLPHL 3571

Table 3. Cause of death in NLPHL and CHL patients There have been very few prior studies evaluating the outcome of NLPHL (n 5 10) CHL (n 5 17) patients with advanced-stage NLPHL. The largest study reported by Cause of death No. % No. % the GHSG described 82 patients with advanced-stage NLPHL (stage IIB with risk factors and stage III to IV) who were evaluated as part HL 1 10 8 47 Aggressive NHL 4 40 0 of a larger retrospective study comparing patients with all stages 15 Secondary cancers 1 10 3 18 of NLPHL or CHL treated on GHSG trials from 1988 to 2002. Cardiac 4 40 6 35 Treatments were heterogeneous and included cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)-ABVD 1 RT, therapy only because of a poor PS. Four patients subsequently died COPP-ABV-ifosfamide, methotrexate, etoposide, and prednisolone 1 of aggressive lymphoma. However, for the surviving patients, (IMEP) RT, and bleomycin, etoposide, doxorubicin, cyclophos- there were no subsequent lymphoma relapses. phamide, vincristine, and procarbazine (BEACOPP) baseline or escalated (or combined) 6 RT. In that study, the median follow-up was only 4.2 years, limited-stage and advanced-stage patients were ana- lyzed together for many of the outcome comparisons, and the type of Discussion lymphoma relapse was not reported. The FFTF (events were relapse or progression, death, and lack of a complete response) was similar in Patients with NLPHL infrequently present with advanced-stage dis- patients with advanced-stage NLPHL and CHL (4.2-year HL-FFTF, ease and as a result, there is limited information regarding outcome, 77% vs 75%). This end point is best compared with our TTP definition risk of transformation and optimal therapy. Interpretation of older in which we demonstrated a similar 25% lymphoma relapse rate in studies remains challenging because they often lack pathologic re- both HLsubtypes at 5 years (Table 2); however, withlonger follow-up, review using modern diagnostic criteria or follow-up is too short the TTP curves diverge because of late lymphoma relapses, some of given the propensity for late relapse. which represent secondary aggressive lymphoma (Figure 2). In the We sought to compare the outcome of patients with advanced- GHSG study, the OS was found to be superior in NLPHL; however, stage NLPHL primarily treated with ABVD-like chemotherapy with patients with advanced-stage disease were not evaluated separately. a matched cohort of patients with advanced-stage CHL in an effort to The ETFL evaluated 44 patients with advanced-stage NLPHL highlight differences in the natural history. Although relapses from who were mostly treated in the 1980s; thus, almost half the patients HL were similar in both cohorts, late relapses were more common in received MOPP alone. With a median follow-up of 6.8 years for the NLPHL cohort, confirming observations in other series.1 Male patients of all stages, the 8-year HL-FFTF was 62% and 24% in stage gender was associated with an increased risk of NLPHL relapse. III (n 5 31) and stage IV (n 5 13) patients, respectively, with A recent study from the German Hodgkin Lymphoma Study Group corresponding OS estimates of 94% and 41%.1 Patients with stage IV (GHSG) also found that male gender was associated with an in- disease are exceedingly rare and represent only 5% of all patients creased risk of relapse and/or progression in NLPHL patients in with advanced-stage disease in our study. In the ETFL analysis, addition to low albumin.14 Further, variant histopathologic growth almost half the patients with stage IV disease had liver involvement pattern, as previously defined by Fan and colleagues as the on clinical grounds but confirmatory biopsies were not routinely presence of LP cells outside of B-cell nodules or reduced numbers undertaken. Given the rarity of liver involvement with NLPHL in our of non-neoplastic B cells within the nodules, was associated with series and most other series, it seems likely that the EFTL patients advanced-stage disease and an inferior progression-free survival harbored aggressive disease that was not optimally treated with (PFS) compared with typical NLPHL histology, but whether this HL-directed therapies. Again, the type of lymphoma relapse was reflects relapse from NLPHL or the development of secondary not reported. aggressive lymphoma is unknown.15 There is continued debate regarding the optimal chemotherapy in Not surprisingly, in our analysis, the development of secondary NLPHL and whether it should be treated similarly to CHL. This lack aggressive lymphoma occurred exclusively in NLPHL with a cumu- of consensus is highlighted in the diversity of choices recommended lative risk at 15 years of 24%, but this also translated into an inferior in both the European Society for Medical Oncology (ESMO) and the TTP compared with CHL, an end point which comprises all lym- National Comprehensive Cancer Network (NCCN) guidelines for phoma relapses (P 5 .040). Considering only patients treated with advanced-stage disease.16,17 The ESMO guidelines for NLPHL tend ABVD-like therapy, by 10 years, approximately 40% have relapsed to follow recommendations for CHL with either ABVD or escalated with either NLPHL or secondary aggressive lymphoma. Those with BEACOPP as treatment options. In contrast, the NCCN recommen- splenic involvement at diagnosis have a 10-year TTP of only 48% dations are diverse and include ABVD as well as cyclophosphamide, compared with 71% for those without splenic involvement, sug- gesting that ABVD may be inadequate in this subgroup, possibly Table 4. P values for univariate analysis of risk factors for because of the increased risk of harboring occult aggressive lym- transformation to secondary aggressive NHL, HL-FFTF, and TTP phoma. Interestingly, in 3 patients, the spleen was removed during TTT to HL-FFTF TTP staging laparotomy at the time of the initial diagnosis of NLPHL Clinical secondary (relapse (relapse all and thus, the sole reason cannot be the presence of occult aggressive feature NHL NLPHL) lymphoma) OS disease in the spleen. The cumulative incidence of aggressive lym- Male gender .149 .040 .113 .504 phoma in our study is higher than that reported in the literature. This Age $45 years .703 .466 .469 .865 probably reflects our focus on patients with advanced-stage disease in B symptoms .412 .688 .239 .043 addition to mature follow-up (median, .11 years), because this event PS $2 .289 .0007 .058 .025 can occur decades after the original diagnosis in addition to patho- Splenic disease .019 .760 .001 .521 logic review at the time of lymphoma relapse. Notably, a trend to Mass $5 cm .011 .194 .480 .645 a worse OS was observed in patients who developed transformed Elevated LDH .198 .306 .904 .493 ABVD-like .755 .147 .744 .728 lymphoma. From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

3572 XING et al BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23

Figure 4. TTP in patients treated with ABVD by spleen involvement at diagnosis of NLPHL.

vincristine, and prednisone (CVP); CHOP; and dose-adjusted etopo- patients, half of which had advanced-stage disease, are now mature.20 side, prednisone, vincristine, cyclophosphamide, and doxorubicin With a high relapse rate observed with the standard treatment (DA-EPOCH). Further, noncurative approaches such as use of administered once per week for 4 weeks (5-year PFS, 39%), the single-agent rituximab, palliative RT, or observation have also been protocol was amended to include maintenance rituximab every 6 suggested for those with asymptomatic disease.16 months for 2 years. Although the latter was associated with an Some studies have suggested that alkylator-based chemotherapy improved 5-year PFS of 58.9%, these results appear inferior to those may be superior in NLPHL,18 possibly reflecting a bias that NLPHL achieved with combination chemotherapy, and this approach does not is best managed similarly to indolent NHL. A pooled study of 37 appear to be curative. Secondary transformation to aggressive B-cell patients with advanced-stage NLPHL treated on Cancer and lymphoma was noted in 9 (39%) of 23 of the relapsed patients, Group B (CALGB) studies and at the Dana-Farber Cancer Center/ including both DLBCL and THRLBCL. Interestingly, 6 of 9 of these Joint Center for Radiation Therapy (DFCI/JCRT) described a 75% patients had infradiaphragmatic involvement at study entry, but failure rate in patients treated with ABVD or etoposide, vinblastine, splenic involvement was not documented. More recently, the MD and doxorubicin (EVA) compared with only 32% in patients treated Anderson Cancer Center (MDACC) evaluated the outcome of 15 with MOPP or MOPP/ABVD.18 However, interpretation is challeng- NLPHL patients treated with rituximab plus CHOP (R-CHOP) ing because of the small number of patients—only 12 patients were chemotherapy (advanced stage, n 5 11).22 With a median follow-up treated with either ABVD or EVA (which subsequently was shown to of 42 months, there have been no relapses or transformations. Al- be inferior to ABVD19)—as well as the inclusion of patients who had though the follow-up is short and the number of patients small, these relapsed following RT (which may represent a different risk group). findings support further study of R-CHOP chemotherapy for patients Furthermore, the patients included in that retrospective analysis were with NLPHL, especially for those with splenic and perhaps infra- diagnosed in an era prior to routine immunophenotyping and thus, the diaphragmatic involvement at diagnosis. Longer follow-up will be diagnosis of NLPHL may be unreliable. necessary to determine whether R-CHOP can alter the natural At the BCCA, the treatment approaches for NLPHL and CHL history of NLPHL, including late NLPHL relapses, sufficiently to have been similar, and thus, in recent years, the large majority of guide usage for all patients. patients have been treated with ABVD-like chemotherapy. Gene ex- In summary, this analysis highlights the distinct disease behavior pression studies support a close relatedness of NLPHL with CHL but of NLPHL compared with CHL and the need for repeat biopsy at also with THRLBCL, highlighting its unique biology.20 Amorere- relapse as well as long-term surveillance. With mature follow-up, the cent study by Hartmann et al21 compared the gene expression profile risk of lymphoma relapse is higher in NLPHL than in CHL, and of microdissected tumor cells from NLPHL, THRLBCL-like NLPHL splenic involvement represents an inherent risk factor for the future (defined as having at least one typical NLPHL nodule), and THRLBCL development of transformed aggressive lymphoma. Our study pro- and found significant molecular overlap between these entities. Pairwise vides a historical comparison of the outcome of advanced-stage supervised comparisons also demonstrated very few differentially NLPHL with primarily ABVD-like therapy and provides a rationale expressed genes, and it is speculated that the composition of the for further evaluation of CHOP with the addition of rituximab, given microenvironment defines these entities, which may in turn reflect the strong expression of CD20. host immune status.21 In our analysis, there was an excess of lym- phoma relapses in NLPHL compared with CHL using ABVD-like chemotherapy which, in some instances, resembled THRLBCL. Further pathologic studies are needed to define which NLPHL Authorship patients may be better suited for aggressive lymphoma therapies. Given that LP cells are strongly CD20 positive, rituximab has Contribution: K.X. participated in study design, chart review, data been evaluated in NLPHL. The results from a phase 2 study collection and manuscript writing; K.J.S. conceived of the study, evaluating single-agent rituximab in 39 relapsed and newly diagnosed participated in study design, data collection, statistical analysis, data From bloodjournal.hematologylibrary.org by guest on July 21, 2014. For personal use only.

BLOOD, 5 JUNE 2014 x VOLUME 123, NUMBER 23 SURVIVAL OF ADVANCED-STAGE NLPHL 3573 interpretation, and manuscript writing; J.M.C. participated in study Conflict-of-interest disclosure: K.J.S., L.H.S., J.M.C., and R.D.G. design; M.A.-M. participated in the chart review; A.L. performed the have received research funding from Roche. The remaining authors statistical analysis; R.D.G. and B.S. performed pathologic review; and declare no competing financial interests. all authors contributed to patient data and manuscript review and read Correspondence: Kerry J. Savage, 600 West 10th Ave, Vancouver, and approved the final manuscript. BC, Canada V5Z 4E6; email: [email protected]. References

1. Diehl V, Sextro M, Franklin J, et al. Clinical 7. Jaffe ES, Harris NL, Stein H; World Health and classical Hodgkin’s lymphoma: presentation, course, and prognostic factors Organization. Pathology and Genetics: Tumours a comprehensive analysis from the German in lymphocyte-predominant Hodgkin’s disease of Haematopoietic and Lymphoid Tissues. Lyon, Hodgkin Study Group. J Clin Oncol. 2008;26(3): and lymphocyte-rich classical Hodgkin’s disease: France: IARC Press; 2001. 434-439. report from the European Task Force on 8. Macpherson N, Klasa RJ, Gascoyne R, O’Reilly 16. National Comprehensive Cancer Network. NCCN Lymphoma Project on Lymphocyte-Predominant SE, Voss N, Connors JM. Treatment of elderly Practice Guidelines in Oncology. Hodgkin Hodgkin’s Disease. J Clin Oncol. 1999;17(3): Hodgkin’s lymphoma patients with a novel 5-drug lymphoma. version 2. Updated 2012. http://www. 776-783. regimen (ODBEP): a phase II study. Leuk nccn.org/professionals/physician_gls/f_ 2. Anagnostopoulos I, Hansmann ML, Franssila K, Lymphoma. 2002;43(7):1395-1402. guidelines.asp#site. Accessed October 8, 2012. et al. European Task Force on Lymphoma project 9. Canellos GP, Anderson JR, Propert KJ, et al. 17. Eichenauer DA, Engert A, Dreyling M; ESMO on lymphocyte predominance Hodgkin disease: Chemotherapy of advanced Hodgkin’s disease Guidelines Working Group. Hodgkin’s lymphoma: histologic and immunohistologic analysis of with MOPP, ABVD, or MOPP alternating with ESMO Clinical Practice Guidelines for diagnosis, submitted cases reveals 2 types of Hodgkin ABVD. N Engl J Med. 1992;327(21):1478-1484. treatment and follow-up. Ann Oncol. 2011; disease with a nodular growth pattern and 10. Cheson BD, Pfistner B, Juweid ME, et al; 22(Suppl 6):vi55-vi58. abundant lymphocytes. Blood. 2000;96(5): International Harmonization Project on 1889-1899. 18. Canellos GP, Mauch P. What is the appropriate Lymphoma. Revised response criteria for systemic chemotherapy for lymphocyte- 3. Orlandi E, Lazzarino M, Brusamolino E, et al. malignant lymphoma. J Clin Oncol. 2007;25(5): predominant Hodgkin’s lymphoma? J Clin Oncol. Nodular lymphocyte predominance Hodgkin’s 579-586. 2010;28(1):e8. disease: long-term observation reveals 11. Kaplan EL, Meier P. Nonparametric estimation a continuous pattern of recurrence. Leuk from incomplete observations. J Am Stat Assoc. 19. Canellos GP, Gollub J, Neuberg D, Mauch P, Lymphoma. 1997;26(3-4):359-368. 1958;(53):457-481. Shulman LN. Primary systemic treatment of advanced Hodgkin’s disease with EVA 4. Al-Mansour M, Connors JM, Gascoyne RD, 12. Hasenclever D, Diehl V. A prognostic score for (etoposide, vinblastine, doxorubicin): 10-year Skinnider B, Savage KJ. Transformation to advanced Hodgkin’s disease. International follow-up. Ann Oncol. 2003;14(2):268-272. aggressive lymphoma in nodular lymphocyte- Prognostic Factors Project on advanced predominant Hodgkin’s lymphoma. J Clin Oncol. Hodgkin’s disease. N Engl J Med. 1998;339(21): 20. Advani RH, Horning SJ, Hoppe RT, et al. Mature 2010;28(5):793-799. 1506-1514. results of a phase II study of Rituximab therapy for nodular lymphocyte-predominant Hodgkin 5. Biasoli I, Stamatoullas A, Meignin V, et al. 13. O’Reilly SE, Klimo P, Connors JM. The evolving lymphoma. J Clin Oncol. 2014;32(9):912-918. Nodular, lymphocyte-predominant Hodgkin role of etoposide in the management of lymphoma: a long-term study and analysis of and Hodgkin’s disease. Cancer. 21. Hartmann S, D¨oringC, Jakobus C, et al. transformation to diffuse large B-cell lymphoma in 1991;67(1 Suppl):271-280. Nodular lymphocyte predominant hodgkin a cohort of 164 patients from the Adult Lymphoma 14. Hartmann S, Eichenauer DA, Pl¨utschowA, et al. lymphoma and T cell/histiocyte rich large B cell Study Group. Cancer. 2010;116(3):631-639. The prognostic impact of variant histology in lymphoma—endpoints of a spectrum of one disease? PLoS ONE. 2013;8(11):e78812. 6. Rueffer U, Josting A, Franklin J, et al; German nodular lymphocyte-predominant Hodgkin Hodgkin’s Lymphoma Study Group. Non- lymphoma: a report from the German Hodgkin 22. Fanale MA, Lai C, McLaughlin P, et al. Outcomes Hodgkin’s lymphoma after primary Hodgkin’s Study Group (GHSG). Blood. 2013;122(26): of nodular lymphocyte predominant Hodgkin’s disease in the German Hodgkin’s Lymphoma 4246-4252, quiz 4292. lymphoma (NLPHL) patients treated with Study Group: incidence, treatment, and 15. Nogov´aL, Reineke T, Brillant C, et al; German R-CHOP [abstract]. Blood. 2010;116(21). prognosis. J Clin Oncol. 2001;19(7):2026-2032. Hodgkin Study Group. Lymphocyte-predominant Abstract 2812.