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 lymphoma 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. 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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 doxorubicin, 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 aggressive lymphoma, 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, vincristine, 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.