HEMATOLOGY Board Review Manual

Volume 7, Part 4 November 2012 HEMATOLOGY Board Review Manual Advanced-Stage and Relapsed/ Refractory Hodgkin Lymphoma

HEMATOLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE The Hospital Physician Hematology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in hematology. Each manual reviews a topic essential to the current practice of hematology. PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Bruce M. White SENIOR EDITOR Robert Litchkofski EXECUTIVE VICE PRESIDENT Barbara T. White EXECUTIVE DIRECTOR OF OPERATIONS Jean M. Gaul Advanced-Stage and Relapsed/Refractory Hodgkin Lymphoma Series Editor: Eric D. Jacobsen, MD Instructor in Medicine, Harvard Medical School; Attending Physician, Dana-Farber Cancer Institute, Boston, MA Contributors: Jasleen Randhawa, MD Fellow, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI Sai Ravi Pingali, MD Fellow, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI Timothy S. Fenske, MD Associate Professor of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI Table of Contents NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Introduction...2 Presentation, Initial Evaluation, and Prognosis..2 Treatment...3 Summary...10 References...10 Cover Illustration by Kathryn K. Johnson Copyright 2012, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. www.turner-white.com Hematology Volume 7, Part 4 1

HEMATOLOGY BOARD REVIEW MANUAL Advanced-Stage and Relapsed/ Refractory Hodgkin Lymphoma Jasleen Randhawa, MD, Sai Ravi Pingali, MD, and Timothy S. Fenske, MD INTRODUCTION Hodgkin s lymphoma, previously known as Hodgkin s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathological and epidemiological features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells. 1 HL is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells usually account for only 0.1% to 10% of the cells, and these HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes which then constitute the majority of tumor cellularity. 2 Despite the disease first being described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center derived B cells. Due to the development of highly effective therapies, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article, the second in a 2-part series on management of Hodgkin lymphoma, reviews the clinical features and treatment options for advancedstage and relapsed/refractory Hodgkin lymphoma. The initial article in this series reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with limited-stage Hodgkin lymphoma. 3 PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS Overall, classical Hodgkin lymphoma (chl) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease. 4 A mediastinal mass is seen in most patients with nodular sclerosis chl, at times showing the characteristics of bulky (>10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with chl, but 50% of advanced-stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from chl by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the limited-stage Hodgkin lymphoma article. 3 For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early favorable, early unfavorable, and advanced stage. It should be noted that in the German Hodgkin Study Group (GHSG), only stage III/IV patients are considered advanced stage, while in North American clinical trials (until recent years), stage I/II patients with bulky mediastinal disease have generally been enrolled on advanced-stage Hodgkin lymphoma protocols. The prognosis of advanced-stage Hodgkin lymphoma patients can be refined using a prognostic index commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years, stage IV disease, hemoglobin <10.5 g/dl, white blood cell (WBC) count >15,000/µL, lymphopenia (absolute lymphocyte count of <600 cells/µl or lymphocytes <8% of WBC count), and serum albumin <4 g/dl (Table). 5 In the original study by Hasenclever and Diehl, 5 the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency 2 Hospital Physician Board Review Manual www.hpboardreview.com

Table. International Prognostic Index and Prognosis in Advanced Hodgkin Lymphoma Number of Risk Factors GHSG 5-Year FFP (%) BCCA 5-Year FFP (%) GHSG 5-Year OS (%) BCCA 5-Year OS (%) 0 84 88 89 98 1 77 84 90 97 2 67 80 81 91 3 60 74 78 88 4 51 67 61 85 5 42 62 56 67 0 3 70 81 83 93 4 7 47 65 59 78 Risk factors: age 45 years; male gender; stage IV; hemoglobin <10.5 g/dl; white blood cell count 15,000 cells/µl; lymphocyte count <600 cells/µl (or <8%); serum albumin <4 g/l. BCCA = British Columbia Cancer Agency; FFP = freedom from progression; GHSG = German Hodgkin Study Group; OS = overall survival. Data is based on studies from the GHSG 5 and BCCA. 6 found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%. 6 This improvement is likely a reflection of improved therapy and supportive care. Given these improved outcomes, the IPS alone may not be the most robust tool to select patients for whom therapy should deviate from the standard of care. Instead, ongoing trials may eventually define a clear role for interim positron emission tomography (PET)/computed tomography (CT) scan to identify patients for whom more aggressive therapy is needed. TREATMENT Treatment of advanced-stage or relapsed/refractory LPHL generally follows the approach for chl. The one exception is that, because of generally high expression of CD20 in LPHL (in contrast to chl), incorporation of rituximab into salvage therapy may be of benefit in LPHL. 7 Except where indicated, the remainder of this article is focused on the treatment of advanced-stage and relapsed/refractory chl. FRONTLINE THERAPY FOR ADVANCED-STAGE HODGKIN LYMPHOMA First-line Chemotherapy Chemotherapy plays an essential role in the treatment of advanced-stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced-stage patients. The complete remission (CR) rate was 81%, 36% of whom relapsed later. 8 This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias. 9,10 This led to development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). 11 In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66% 73%). 12 In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advancedstage chl in the United States. In hopes of further minimizing toxicity, the Stanford V regimen was developed. 13 Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates. 14,15 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy to original sites of disease greater than 5 cm in size and contiguous sites. Another regimen which has been studied extensively for advanced-stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, www.hpboardreview.com Hematology Volume 7, Part 4 3

doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study, the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ ABVD in advanced-stage Hodgkin lymphoma. 16 All arms of the study included 30 Gy radiation therapy (RT) to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. The HD 2000 trial 17 as well as a recently published trial by Viviani et al 18 showed an improved FFS at 5 to 7 years, but a survival benefit was not demonstrated. These studies also confirmed a higher rate of toxicities associated with the escalated BEACOPP regimen. In the United States, ABVD (6 8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) or Stanford V are considered appropriate as well. 19 In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% and OS of 86% to 88%. 15,18,20 Patients over age 60 often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma. 21 Radiation Therapy in Frontline Treatment In patients with advanced-stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may also be incorporated into frontline therapy to improve local control. However, this has not been proven to provide a survival benefit. The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced-stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV. 22 Patients in CR were randomized to receive either no further treatment or IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. Among the patients in partial remission after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced-stage Hodgkin lymphoma who had a residual lesion by CT (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen. 23 The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. Therefore, restricting IFRT to sites that remain PET-positive after completing chemotherapy may allow for the avoidance of RT in many patients. This approach was taken in the GHSG HD15 trial in which advanced-stage patients were treated with 3 variations on the BEACOPP regimen. Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET-positive, it was treated with 30 Gy of IFRT. Patients with a residual lesion by CT that was PET-negative had an identical outcome to the patients with a complete response by CT (93% PFS at 4 years). Of those who were PET-positive after chemotherapy, a 4-year PFS of 86% was seen. Furthermore, with this approach the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study, with no apparent loss in efficacy. 24 Upfront Stem Cell Transplantation To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with autologous stem cell transplantation (autosct) has been explored as part of frontline therapy. While this has been shown to be feasible in such patients, 25 randomized trials have not shown a clear benefit in terms of FFS or OS with upfront autosct. 26,27 Therefore autosct is not 4 Hospital Physician Board Review Manual www.hpboardreview.com

considered a standard component of frontline therapy for chl. RELAPSED/REFRACTORY HODGKIN LYMPHOMA Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to either experience primary induction failure or a relapse after attaining remission with frontline therapy. 3,28 Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and autosct. For patients not felt to be candidates for autosct, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents, and/or participation in clinical trials. Conventional Second-Line Chemotherapy Numerous conventional regimens have been shown in phase II studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylatorbased regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient s age, performance status, comorbidities, and whether autosct is being considered. In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide), 29 DHAP (dexamethasone, cisplatin, high-dose cytarabine), 30 ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin), 31 GDP (gemcitabine, cisplatin, dexamethasone) 32, and GCD (gemcitabine, carboplatin, dexamethasone) 33 are all considered appropriate second-line therapy options for patients being considered for autosct, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41% and toxic death rates generally well below 5%. However, these regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. Other gemcitabinebased regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also good choices for secondline therapy, with response rates of 70% to 80%. 34,35 Stem cell collection remains feasible after both IGEV and GVD as well. Some centers, particularly in Europe, favor aggressive salvage regimens such as mini-beam (carmustine, etoposide, cytarabine, melphalan) 36 or dexa-beam (BEAM plus dexamethasone). 37 These regimens, however, are associated with significant hematologic toxicity and high (2% 5%) treatment-related mortality. For patients not being considered for autosct, or those for whom platinum-based salvage therapy was ineffective, gemcitabine-based regimens such as IGEV and GVD may be effective. 34,35 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients. 35 ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP. 38 40 In practice, however, most patients who present with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered. However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be autosct candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. 41 43 Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer. 44,45 Autologous Stem Cell Transplantation Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed Hodgkin lymphoma treated by autosct as compared to those receiving conventional chemotherapy alone. 37,46,47 Overall, for relapsed disease, one can expect an www.hpboardreview.com Hematology Volume 7, Part 4 5

approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for autosct patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47% 54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from autosct, including an OS benefit. 47 One European prospective randomized trial has been conducted comparing conventional salvage therapy to autosct. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa- BEAM. Those with chemosensitive disease were then randomized to either 2 more cycles of dexa-beam or high-dose BEAM with autosct. AutoSCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone. 37 This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with autosct. For patients with late relapse (>1 year after completion of primary therapy), autosct was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of autosct in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of autosct (53% versus 10%), again with no difference in OS. 46 The lack of OS benefit seen in these studies suggests that autosct at first or second relapse provides comparable outcomes. AutoSCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatmentrelated mortality with autosct is now in the 1% to 3% range at centers that perform the procedure routinely. For all of these reasons, autosct is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for autosct as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. The optimal conditioning regimen for autosct for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent autosct using either a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen. 48 Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI, 49 chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases. 50 IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following autosct. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with autosct alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70% 73% versus 40% 56%). 51,52 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following autosct in relapsed/refractory Hodgkin lymphoma. Prognostic factors associated with outcome with autosct. The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo autosct is the disease status at transplant. 50,53 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively. 53 The duration between remission and relapse also has important prognostic significance. Late relapse (>1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse. 37 Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status. 29,54 56 This prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-autosct versus 33% in those whose functional imaging remained positive. 57 Very similar findings have been reported by other groups. 58,59 Functional imaging pre-autosct to guide therapy. It has been observed that PET status pre-autosct can 6 Hospital Physician Board Review Manual www.hpboardreview.com

stratify patients into those likely or unlikely to achieve a long-term remission post-autosct. Based on this observation, it has been hypothesized that giving patients who continue to have active disease by PET following second-line chemotherapy additional (third-line) therapy pre-autosct (in hopes of achieving a PET-negative state) may improve the patient s chance for long-term remission post-autosct. In a recent study, patients with relapsed or refractory chl were treated with ICE therapy. Those who had a response but remained PET-positive were treated with 2 cycles of GVD and a repeat PET scan was performed; those without disease progression underwent autosct. Those who became PET-negative after GVD had a 5-year EFS that was similar to those who became PET-negative after ICE. 60 This suggests that it may be worthwhile to administer conventional third-line therapy for those remaining PET-positive prior to autosct. Whether incorporating newer agents such as brentuximab into salvage therapy will further improve outcomes with autosct is not yet known. Primary Refractory Hodgkin lymphoma Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients. 9,61 Given these poor outcomes with conventional salvage therapy, autosct is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with autosct. Patients with poor functional status at time of transplant, age >50 years, and failure to attain a temporary remission had a 0% 5-year OS as compared to 55% in patients without any of these risk factors. 62 A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years. 53 Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following autosct. Salvage Radiotherapy The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT. 63 Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. 64 The 10-year FFTF and OS rates were 33% and 46%, respectively. Factors associated with improved outcome were age <50 years, CR to the last chemotherapy regimen, lack of B symptoms, and absence of extranodal disease. 64 Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms. 65 RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. Novel Agents for Relapsed and Refractory Hodgkin Lymphoma Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and antibody-drug conjugates that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. Brentuximab vedotin. Brentuximab vedotin is an antibody-drug conjugate (ADC) consisting of an anti- CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma (ALCL). Upon binding to CD30, the ADC/ CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. 66 MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. Two phase I trials evaluated brentuximab in weekly 67 and every 3-week 68 regimens. The objective response rate (ORR) with the weekly regimen was 59%, with 34% achieving CR. With the 3-week regimen, the CR rate was 24% with an ORR of 38%, with some degree of tumor regression seen in 86% patients. These studies were followed by phase II studies in CD30-positive Hodgkin lymphoma and ALCL which showed an ORR of 75% (including a CR rate of 34%) in Hodgkin lymphoma. 69 The GHSG recently reported their experience with brentuximab as a single agent in 45 patients with relapsed or refractory CD30-positive Hodgkin lymphoma, 39 of whom had previously undergone stem cell transplant. An overall response rate of 60% was seen, with a 22% CR rate. The median duration of response was 8 months. 70 Based on the results of the phase I and II trials, the www.hpboardreview.com Hematology Volume 7, Part 4 7

FDA approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after failed autosct, or in patients who are not autosct candidates and who have received at least 2 prior chemotherapy regimens. A phase III randomized, double-blind, placebo-controlled trial is ongoing to evaluate the role of brentuximab in patients at high risk for residual Hodgkin lymphoma post-autosct. Brentuximab is also being evaluated in combination with other chemotherapy agents in the frontline and second-line settings, and prior to allogeneic stem cell transplant (allosct; see below). In addition, administration of brentuximab appears to remain safe and effective for patients with recurrent disease after allosct. 71 Rituximab. Rituximab is a chimeric anti-cd20 monoclonal antibody used widely in B-cell non-hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with overall response rates ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10 to 33 month range. 72,73 In chl, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell. 74,75 As a result, ongoing studies are evaluating the potential benefit of adding rituximab to standard chemotherapy regimens in advanced-stage chl. Lenalidomide. Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase II study by Fehniger et al included 35 patients, 87% of whom had previously undergone SCT and 55% of whom were refractory to the last therapy. 76 All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved partial response, and 5 had stable disease lasting more than 6 months, for an overall response rate of 19% and a cytostatic overall response rate of 33%. The median duration of CR/ partial remission was 6 months, with the median timeto-treatment failure in responders (including those with stable disease >6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. Overall response rate was noted to be 50% with 6 patients with stable disease and 5 patients achieving partial remission after 2 cycles. 77 Histone deacetylase (HDAC) inhibitors. Several other novel agents have been evaluated or are undergoing evaluation for relapsed and refractory Hodgkin lymphoma as well. These include the HDAC inhibitors MGCD0103 and panobinostat. MGCD0103 is an oral HDAC inhibitor that produced an overall response rate of 35% in relapsed Hodgkin lymphoma. 78 Panobinostat has also shown activity in relapsed/refractory disease, with an overall response rate in the 20% to 38% range. 79 In patients with relapsed and refractory Hodgkin lymphoma following autosct, a tumor burden reduction of 92% with a disease control rate of 79% was seen. 80 In a phase II study of panobinostat in patients with refractory Hodgkin lymphoma or relapse less than 1 year following autosct, an overall response rate of 27% was reported, with an estimated duration of response of greater than 6.9 months. 81 A phase III trial evaluating panobinostat following autosct as a maintenance therapy is ongoing. 82 Mammalian target of rapamycin (mtor) inhibitors. Two mtor inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase II trial in a heavily pretreated group of relapsed/refractory patients. An overall response rate of 47% was seen, with a median time to progression of 7.2 months. 83 Allogeneic Stem Cell Transplantation Patients who relapse after having an autosct generally have a poor outcome, with a median survival of 2 to 3 years after failure of autosct. 84 These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly 8 Hospital Physician Board Review Manual www.hpboardreview.com

an allosct. However, rare patients with late relapse after autosct may be considered for a second autosct, with a minority of such patients achieving a durable remission after the second autosct. 85,86 Because relapse or progressive disease occurs most commonly in the first several months following autosct, patients are more often considered for allosct than a second autosct. Several studies have evaluated allosct in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allosct for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (less than 25%). 87,88 This is likely related to the fact that, historically, most of the patients with Hodgkin lymphoma evaluated for allosct are heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. More recently, several studies have focused on the use of reduced-intensity allosct for relapsed and refractory Hodgkin lymphoma. This approach relies more on a graft-versus-lymphoma effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies on patients with multiply recurrent Hodgkin lymphoma have shown improved rates of treatment-related mortality (8% 16%) but still relatively low rates of long-term PFS (23% 39% at 2 to 4 years). 89 91 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants. 90 Recently, 2 large registry studies have also reported on the outcomes of reduced-intensity allosct in patients with relapsed and refractory Hodgkin lymphoma. 92,93 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatmentrelated mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18% 20% at 2 to 5 years) and OS (28% 37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84% 96% had received 3 or more prior lines of chemotherapy and 62% 89% received a prior autosct), with 47% to 55% of patients chemo-resistant prior to transplant. Based on the single-center and registry data above, a prospective multicenter European phase II trial was conducted to evaluate the benefit of reduced-intensity allosct in Hodgkin lymphoma. 94 Ninety-two patients (86% with prior autosct, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent reduced-intensity conditioning with fludarabine and melphalan, followed by allosct (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic graft-versus-host-disease (GVHD) was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allosct, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, reduced-intensity allosct offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. These studies suggest that outcomes with allosct would improve further if implemented earlier in the course of disease and with a lower burden of disease at transplant. It has therefore been suggested that allosct should be considered soon after failure of autosct is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following autosct were then immediately considered for reduced-intensity allosct. 95 Of these, 122 had a donor identified, and 104 (85%) actually underwent allosct. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allosct. Two-year PFS and OS were superior in the patients undergoing allosct (39% versus 14% and 66% versus 42%, respectively, P < 0.001) with a median follow up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allosct compared with patients who underwent conventional salvage therapies alone. 96,97 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allosct are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. As discussed earlier, brentuximab is highly effective in relapsed and refractory Hodgkin lymphoma patients. However, for most patients, responses to brentuximab last less than 1 year, with only a small minority www.hpboardreview.com Hematology Volume 7, Part 4 9

of patients maintaining response for 2 years or longer. Therefore, for patients who fail autosct, a useful longterm strategy may be to produce a remission with brentuximab, followed by a reduced-intensity allosct. This approach has the theoretical advantages of (1) getting patients to transplant with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (2) applying allosct in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a recent small study suggest that brentuximab may in fact be a very effective bridge to allotransplant. Chen et al 98 reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone autosct) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allosct. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allosct in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes. Future studies should better define the optimal timing and duration of brentuximab therapy in relation to allosct. SUMMARY Currently, cure is possible for the majority of patients diagnosed with advanced-stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation and/or RT. 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Int J Radiat Oncol Biol Phys 2005;63:1538 45. www.hpboardreview.com Hematology Volume 7, Part 4 11