Published Ahead of Print on April 2, 2009 as /theoncologist Salvage Therapy in Hodgkin s Lymphoma

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1 The Oncologist Lymphoma Salvage Therapy in Hodgkin s Lymphoma JASON H. MENDLER,JONATHAN W. FRIEDBERG James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA Key Words. Hodgkin Lymphoma Relapse Refractory Salvage Transplant Disclosures: Jason H. Mendler: None; Jonathan W. Friedberg: Honoraria: Lilly; Research finding: Cephalon, Millennium. Section editor disclosures to come The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. LEARNING OBJECTIVES 1. Describe the most important properties of a salvage chemotherapy regimen and name at least three effective regimens. 2. Identify at least five poor-risk clinical features pre-hdct/asct that reduce the chance for cure and describe an alternative transplant approach that might be more effective. 3. Identify two monoclonal antibodies that have shown activity against relapsed HL and be able to describe the hypotheses for why they are effective. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT Hodgkin s lymphoma (HL) is a commonly cured malignancy. Unfortunately, patients who are refractory to or relapse after first-line treatment pose a significant therapeutic challenge. There is evidence that these patients are best treated with an approach involving salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT/ASCT). This approach may result in cure, with better results in patients with low-risk relapse. In patients with high-risk relapse and refractory disease, HDCT/ASCT is rarely curative. More aggressive transplant approaches have shown promising results in this group and are currently under active investigation. For those relapsing after HDCT/ASCT, there exists a range of therapeutic options, including further salvage chemotherapy, reduced-intensity allogeneic transplantation, monoclonal antibody therapy, and novel agents. All patients in this category should be considered for enrollment in clinical trials. This review discusses the evidence behind the current practice in patients with relapsed or refractory HL. Specifically, the efficacy of various salvage chemotherapy regimens, the risk factors influencing outcome with HDCT/ASCT, and the results with alternative transplant approaches, monoclonal antibody therapies, and novel agents are addressed. We conclude by providing our approach to these patients, with the hope that this will serve as a framework for the practicing oncologist. The Oncologist 2009;14: Correspondence: Jonathan W. Friedberg, M.D., University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, New York 14642, USA Telephone: ; Fax: ; Jonathan_Friedberg@urmc.rochester.edu Received January 1, 2009; accepted for publication February 13, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 2 Salvage Therapy in Hodgkin s Lymphoma INTRODUCTION The majority of patients with Hodgkin s lymphoma (HL) are cured with first-line therapy; however, approximately 15% 20% of patients with stage I II HL and 35% 40% of patients with stage III IV HL and risk factors relapse after first-line therapy [1, 2]. Current practice in patients with relapsed or refractory HL dictates the prompt use of secondline, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT/ ASCT). Whereas this approach is acceptable for patients with favorable-risk relapse, patients with poor-risk relapse or primary refractory disease may benefit more from alternative approaches. Alternative approaches currently under active investigation include tandem autologous stem cell transplants, allogeneic transplants, antibody therapies, and novel agents. The aim of this review is to discuss the current evidence behind the treatment of the relapsed/refractory HL patient, to discuss areas of active investigation, and to detail the approach used at our institution. SALVAGE CHEMOTHERAPY One of the most important goals in the relapsed or refractory HL setting is disease control with salvage chemotherapy. It has been demonstrated in multiple studies that effectiveness in terms of the response to salvage chemotherapy is a major determinant of outcome after HDCT/ ASCT [3 5]. Recently, it was demonstrated that patients with a complete response (CR) prior to transplant had a 5-year progression-free survival (PFS) rate of 79%, compared with 59% for those with a partial response (PR) and 17% for those with resistant disease [6]. In the poor-risk primary refractory population, it was demonstrated that the PFS and overall survival (OS) rates were 62% and 66%, respectively, for patients with chemosensitive disease pretransplant versus 23% and 17%, respectively, for patients with chemoresistant disease [7]. Similar results were reported by Gopal et al. [8], who recently demonstrated a 5-year PFS rate of 17% in patients with chemoresistant disease pretransplant. Although response to salvage chemotherapy has been traditionally measured via the international criteria for non- Hodgkin s lymphomas [9], more recent data suggest that functional imaging (FI) prior to HDCT/ASCT may provide a clearer picture [10]. For instance, in patients with negative FI (measured via positron emission tomography or gallium scan) prior to HDCT/ASCT, the 3-year PFS and OS rates were 69% and 87%, respectively, versus 23% and 58%, respectively, for patients with positive FI [11]. Importantly, FI helped clarify the prognosis in patients with a PR. The 3-year PFS rate in these patients with negative FI was 51%, versus 27% for those with positive FI. This underscores the importance of both choosing an effective salvage regimen and measuring the response appropriately. An effective salvage regimen must have a good toxicity profile, in addition to inducing good disease control. Especially important is a lack of toxicity to hematopoietic stem cells, thus preserving the ability to perform an ASCT promptly after salvage chemotherapy. The optimal choice of a salvage regimen is unclear, because different regimens have not been directly compared with one another. It is difficult to compare these regimens for two reasons. One, HL is a rare disease, making it difficult to accrue enough patients in the relapsed/refractory setting for meaningful prospective, randomized trials. Two, there are numerous salvage regimens that have been demonstrated to have activity in single-arm studies, making it difficult to decide which regimens to compare in larger, prospective studies. Unfortunately, the clinician is left to choose from a variety of reasonable salvage options without clear knowledge of the superiority of one regimen (Table 1). The more commonly used regimens for relapsed/refractory HL include the platinum-based regimens ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), ASHAP (doxorubicin, solumedrol, high-dose cytarabine, and cisplatin), and DHAP (cisplatin, cytarabine, and dexamethasone) [12 14] and the ifosfamide-containing regimen ICE (infused ifosfamide, carboplatin, and etoposide) [15]. ESHAP was evaluated in a prospective study of 22 patients with relapsed or refractory HL. Nine patients achieved a CR and seven had a PR (overall response rate [ORR], 73%). Grade 3 4 myelotoxicity was seen in 13 patients (59%) [14]. ASHAP was evaluated in a prospective study of 56 patients with relapsed or primary refractory HL [13]. There were 19 CRs and 20 PRs (ORR, 70%). Myelosuppression was the main toxicity. DHAP was investigated in a prospective study of 102 patients with relapsed or refractory HL [12]. The response rate was 89% (CR, 21%; PR, 68%). World Health Organization grade 4 leukocytopenia and thrombocytopenia were the main toxicities, occurring in approximately half of the patients. ICE was tested in 65 consecutive patients, 22 with primary refractory HL and 43 with relapsed HL [15]. The majority of these patients also received involved-field radiotherapy (see salvage radiation therapy section below). The ORR was 88%, with myelosuppression being the main toxicity. Gemcitabine-based regimens have also been shown to have good activity against relapsed/refractory HL, with preservation of peripheral blood stem cell (PBSC) mobilization and collection [16]. In addition, they have the advantage of generally being outpatient based. Recently, GVD (gemcitabine, vinorelbine, and pegylated liposomal doxorubicin) was evaluated in 91 patients with relapsed or re-

3 Mendler, Friedberg 3 Table 1. Summary of results with selected salvage chemotherapy regimens pre-asct Salvage regimen n of patients Response rate (%) Complete response rate (%) Successful PBSC collection (%) Outpatient Reference DHAP No [12] ICE No [15] IGEV Yes [18] GVD NR a Yes [17] GDP Yes [19] a All patients intended for ASCT were able to receive it. Abbreviations: ASCT, autologous stem cell transplant; DHAP, cisplatin, cytarabine, and dexamethasone; GDP, gemcitabine, dexamethasone, cisplatin; GVD, gemcitabine, vinorelbine, and pegylated liposomal doxorubicin; ICE, ifosfamide, carboplatin, and etoposide; IGEV, ifosfamide, gemcitabine, and vinorelbine; NR, not reported; PBSC, peripheral blood stem cell. fractory HL that were either ASCT-naïve or had received a prior ASCT [17]. The ORR for all patients was 70%, with a 19% CR rate. The dose-limiting toxicity was mucositis for the transplant-naïve patients and febrile neutropenia for the post-transplant patients. IGEV (ifosfamide, gemcitabine, and vinorelbine) was recently tested prospectively in 91 relapsed or refractory HL patients [18]. Forty-nine patients (53.8%) achieved a CR and 25 patients (27.5%) had a PR for an ORR of 81.3%. Impressively, 60% of the primary refractory patients responded. Adequate PBSC collection was achieved in 78 of 79 (98.7%) mobilized patients and toxicity was primarily myelosuppressive. Kuruvilla and colleagues compared GDP (gemcitabine, dexamethasone, and cisplatin) with mini-beam (carmustine, etoposide, cytarabine, and melphalan), a commonly used salvage regimen, in a retrospective analysis [19]. The ORR to GDP prior to ASCT was 62%, compared with 68% for mini- BEAM (not a statistically significant difference), and the PFS duration was significantly better for patients who received GDP. The proportions of patients for whom the target PBSC number was obtained were 97% after GDP and 57% after mini-beam. Given this and other evidence, salvage regimens containing BEAM, despite good response rates, have fallen out of favor because of greater morbidity, mortality, and stem cell toxicity than with other available regimens [5]. SALVAGE RADIATION THERAPY (SRT) Salvage radiation therapy (SRT) is rarely used alone in relapsed or refractory HL. This is because it is generally assumed that disease recurrence indicates dissemination. That said, in patients who have limited late relapses, without B symptoms and with a good performance status, SRT alone is a reasonable approach in selected patients. This is supported by a retrospective analysis of 100 patients with relapsed disease in localized stages and without risk factors treated with SRT alone [20]. In this group, 77% had a CR, 51% were alive at 5 years, and 28% were disease free at 5 years. Negative prognostic factors included B symptoms, Karnofsky performance status score, and stage. Whereas the 5-year OS rate was 68% in patients with stage I disease, it was only 27% for those with stage III/IV disease. SRT may also be useful in combination with chemotherapy. Moskowitz et al. [15] developed a chemoradiotherapy program in the relapsed/refractory HL setting that incorporates involved field radiotherapy (IFRT) with salvage chemotherapy. Patients received two cycles of ICE and IFRT to nodal sites of disease 5 cm or to residual disease still present after salvage chemotherapy. In this study of 65 patients (22 with primary refractory and 43 with relapsed disease), 88% responded to ICE/IFRT and almost all underwent HDCT/ASCT. At a median follow-up of 43 months, the event-free survival (EFS) and OS rates of those that responded to ICE/IFRT were 68% and 83%, respectively. Of the 17 patients who failed treatment, only three occurred in a site irradiated during the salvage program, suggesting a benefit of the IFRT. EVIDENCE FOR HDCT/ASCT AND LIKELIHOOD OF SUCCESS HDCT/ASCT is now the generally accepted standard of care for patients with primary refractory or first-relapsed HL. Linch and colleagues performed the first randomized, prospective clinical trial comparing traditional salvage chemotherapy with HDCT/ASCT [21]. Forty patients with relapsed or refractory HL were randomized to receive either HDCT with BEAM followed by ASCT or traditional salvage chemotherapy with mini-beam (lower doses of the aforementioned drugs without the need for stem cell support). At 3-years of follow-up, The EFS rate was 53% in the BEAM/ASCT group and 10% in the mini-beam group. A more recent, randomized, prospective trial was reported by

4 4 Salvage Therapy in Hodgkin s Lymphoma Schmitz et al. [22]. One hundred sixty-one patients with relapsed HL (they had to have a prior CR lasting at least 3 months with first-line therapy) were randomized to receive two cycles of Dexa-BEAM (dexamethasone, carmustine, cytarabine, and melphalan) followed by either two more cycles of Dexa-BEAM or BEAM/ASCT. Only patients who exhibited at least a PR after the first two cycles of Dexa- BEAM went on to receive further treatment. At 3 years of follow-up, the rate of freedom from treatment failure was 55% in the BEAM/ASCT group and 34% in the Dexa- BEAM group. These studies demonstrate that HDCT/ ASCT provides better disease control than conventional salvage chemotherapy in the relapsed and refractory HL population. Interestingly, neither of these studies showed a survival benefit with HDCT/ASCT. This may have been a result of the relatively short follow-up, the crossover of many patients initially treated with chemotherapy alone to receive an ASCT, and the relatively smoldering nature of relapsed HL, which can respond to multiple lines of chemotherapy over time. Multiple single-arm studies incorporating both relapsed and refractory HL patients have demonstrated that a salvage approach incorporating HDCT/ ASCT results in durable PFS and OS rates in the range of 40% 50% and 50% 60%, respectively [3, 6, 23 26]. Importantly, patients with refractory disease generally do worse, with durable PFS and OS rates in the range of 15% 32% and 26% 36%, respectively [7, 8, 23, 27, 28]. In addition to refractoriness to initial chemotherapy, several other factors have been identified in the relapsed/ refractory HL setting that predict a worse prognosis. These include multiple relapses, relapse in a prior radiation field, older age, Karnofsky performance status score 90, B symptoms, higher stage, extranodal disease, anemia, and shorter time to relapse. Several groups have demonstrated that the number of adverse risk factors present at relapse is inversely correlated with OS and PFS after HDCT/ASCT. For instance, Stiff et al. [29] showed that patients with two or more of the following three risk factors (extranodal disease, relapse in a previously irradiated field, more than two prior chemotherapy regimens) had a 5-year OS rate of 38%, versus 60% for those with none or one factor. Similarly, Wheeler et al. [30] described three prognostic groups based on the number of extranodal sites, nodular sclerosis histology, poor performance status, short time from diagnosis to transplantation, and the presence of B symptoms. Survival in the three groups was in the range of 19% 82%. Horning et al. [24] identified B symptoms, disseminated bone marrow disease at relapse, and more than minimal disease at the time of transplantation as significant prognostic factors for OS and PFS. Patients with none of these factors had a PFS rate of 85% at 4 years, compared with 41% for patients with one or more of them. Brice et al. [31] used two adverse prognostic factors (end-of-treatment to relapse interval 12 months and extranodal relapse) to predict outcome in a French population of patients receiving ASCT. Patients with zero, one, or two of these factors had 4-year OS rates of 93%, 59%, and 43%, respectively. In a prospective study, Moskowitz et al. [15] demonstrated that B symptoms, extranodal disease, and time to relapse 12 months influenced outcome after ASCT. Patients with none or one of these factors had a 43-month EFS rate of 83%, compared with 27% and 10% for patients with two or three factors, respectively. These studies demonstrate that it is possible to use distinct clinical features at relapse to make general predictions about the likelihood of success with HDCT/ASCT. Patients with refractory disease or poor-risk relapse are unlikely to do well with this modality and should be considered for other options. TANDEM ASCT In order to maximize the amount of deliverable high-dose chemotherapy, tandem ASCTs have been investigated. These approaches generally involve two rounds of HDCT/ ASCT in a span of 1 3 months. In the primary refractory and poor-risk relapsed HL populations, rates of PFS and OS are in the range of 49% 59% and 54% 78%, respectively, with a variable length of follow-up [32 34]. Very recently, a prospective multicenter trial evaluated the efficacy of tandem ASCT in 150 patients with primary refractory and poor-risk relapsed HL (defined as two or more of the following risk factors at relapse: time to relapse 12 months, stage III or IV at relapse, and relapse within previously irradiated sites). This was part of a risk-adapted approach wherein intermediate-risk patients (one or fewer of the risk factors above) received a single ASCT. Using an intent-totreat analysis with a median follow-up of 51 months, the estimated 5-year PFS and OS rates among poor-risk patients were 46% and 57%, respectively. Importantly, patients with disease resistant to cytoreductive chemotherapy had a 5-year OS rate of 46%, significantly better than historical controls. In the intermediate-risk patients receiving a single ASCT, the PFS and OS rates were 73% and 85%, respectively. In this and other studies, tandem transplant-related mortality (TRM) has been acceptable and stem cell collections have been adequate to allow both transplants in the majority of cases. These results suggest that tandem ASCT is superior to single ASCT in poor-risk patients with anything less than a CR to initial salvage chemotherapy. Single ASCT is likely sufficient for the majority of intermediaterisk patients and the subset of poor-risk patients with a CR to initial cytoreductive therapy.

5 Mendler, Friedberg 5 TREATMENT OF RELAPSE AFTER ASCT Relapse after ASCT generally portends a poor prognosis, with a median survival duration in the range of 24 months [35]. There is a small subgroup of patients who will have a longer survival duration in this setting, even without further intensive therapy and stem cell support [36]. Options for patients in this setting include SRT, further chemotherapy, allogeneic stem cell transplant (allo-sct), clinical trials investigating new agents, and second ASCT [37]. ALLO-SCT Allo-SCT has primarily been investigated as salvage therapy after failed ASCT. The potential advantage over ASCT lies in a putative graft-versus-hl effect. Evidence for this effect lies in lower relapse rates among allo-sct recipients than among ASCT recipients in retrospective comparisons, variable reports that chronic graft-versus-host disease confers a protective effect against relapse, and durable remissions induced by donor lymphocyte infusions [38]. Early studies demonstrated that myeloablative allo-sct in relapsed HL carries a TRM rate in the range of 48% 61% [39 43]. Given this unacceptable toxicity, more recent studies have investigated the potential of reduced-intensity conditioning (RIC) regimens. Studies using this approach have demonstrated more acceptable TRM with relatively short-term OS and PFS rates in the range of 48% 56% and 32% 39%, respectively [44, 45]. More recently, two studies evaluated the longer-term efficacy of allo-sct with RIC (allo-ric), with widely variable OS and PFS rates in the range of 28% 51% and 18% 34%, respectively [46, 47]. These differential response rates suggest patient selection is a key factor to success. Similar to ASCT, sensitivity to salvage chemotherapy prior to allo-ric is an important predictor of outcome. For this reason, a double-transplantation strategy consisting of HDCT/ASCT followed by allo-ric was developed and was demonstrated to be feasible in a very small number of heavily pretreated HL patients [48]. Its current utility in treating HL patients is unclear. In summary, allo-ric is a reasonable option for the young HL patient with a suitable donor who has relapsed after ASCT. An area of active interest is whether this approach is superior to ASCT at first relapse in high-risk relapsed and primary refractory HL patients. MONOCLONAL ANTIBODY THERAPY The two monoclonal antibodies that have been studied in relapsed/refractory HL target CD30 and CD20. CD30 is a member of the tumor necrosis factor family, is expressed on the surface of Reed Sternberg (RS) cells, and is not expressed in most normal tissues. Signaling through this receptor is thought to promote the survival and proliferation of RS cells [49]. Normal B cells, expressing CD30 ligand, are a major cellular component of lymph nodes affected by HL. It is speculated that these B cells promote the survival of RS cells, at least in part via CD30 signaling. Early-phase clinical studies of anti-cd30 monoclonal antibodies in heavily pretreated patients with HL have demonstrated them to be largely well tolerated. They have shown limited, albeit some, single-agent activity. In the largest phase II study conducted to date, four of 63 patients treated had a clinical response and several more had stable disease [50]. A study performed by the Cancer and Leukemia Group B combining this antibody with a gemcitabine-based chemotherapy regimen was closed early because of unexpected severe pulmonary toxicity [51]. More recently, anti-cd30 antibodies conjugated to monomethyl auristatin E, a potent antitubulin agent, were tested in heavily pretreated HL patients [52]. They were generally well tolerated, with 86% of patients achieving some degree of tumor reduction and 20% achieving a CR. A multicenter phase II study of this agent is now under way to confirm these exciting preliminary results. Rituximab, a monoclonal antibody against CD20, has also been studied in heavily pretreated HL patients. It was demonstrated to have single-agent activity (22% clinical response) and to be effective in combination with gemcitabine (48% clinical response) [53, 54]. This is somewhat surprising given that CD20 expression is absent on RS cells in the majority of HL patients. As mentioned above, CD20 B cells make up much of the microenvironment surrounding RS cells and are thought to promote their survival. It is likely that rituximab exerts its effects in HL, at least in part, through depletion of these supporting B cells. Interestingly, it was recently shown that HL stem cells may express the CD20 antigen, providing another possible target for rituximab. While the results of these studies hold promise, the optimal role of these antibodies in the treatment of the relapsed/refractory HL patient remains to be determined. NOVEL AGENTS Constitutive activation of the transcription factor nuclear factor (NF) B has been demonstrated to be important to the survival of RS cells. As such, approaches have been designed to inhibit its activity. Bortezomib is a proteasome inhibitor that is able to stabilize inhibitor of B, a molecule that inhibits NF B activity. It was thus hypothesized that bortezomib would lead to the death of RS cells in HL patients and a clinical response. Unfortunately, several earlyphase clinical studies of bortezomib have shown that it has no activity in HL [55 57]. It is unclear why this approach is ineffective.

6 6 Salvage Therapy in Hodgkin s Lymphoma Relapsed/refractory HL Salvage with ICE No response Response (at least PR) Alternative salvage regimen No response HDCT/ASCT Response (at least PR) Alternative salvage regimen +/- experimental treatment; consider XRT No response Consider XRT Response (at least PR) Single agents or clinical trials of novel therapies; consider XRT Another promising approach involves histone deacetylase inhibitors (HDACs), molecules that alter gene expression globally through changes in chromatin structure. Preliminary results suggest that the oral single agent MGCD0103, an HDAC inhibitor, has significant antitumor activity in heavily pretreated HL patients, with acceptable toxicity [58]. Lenalidomide, an approved antineoplastic agent for multiple myeloma and myelodysplastic syndrome, is currently being investigated as a single agent in patients with HL who have failed or are not eligible for ASCT. Results from the first stage of a prospective, multicenter, phase II study showed that, of the 15 patients initially treated, four responded (one CR and three PRs) [59]. That study is now moving to its second stage. CONCLUSIONS Allo-SCT candidate? Reduced-intensity allo-sct Figure 1. Our approach to the relapsed/refractory HL patient. Abbreviations: allo-sct, allogeneic stem cell transplantation; HDCT/ASCT, high-dose chemotherapy and autologous stem cell transplant; HL, Hodgkin s lymphoma; ICE, ifosfamide, carboplatin, and etoposide; PR, partial response; XRT, radiotherapy. Yes Future Directions The current standard of care for patients with relapsed or refractory HL results in cure approximately 50% of the time. There are many unanswered questions, the answers to which may improve outcomes. What truly is the optimal first-line salvage regimen? How necessary is a metabolic CR on FI in all patients pre-transplant? Should we be transplanting higher-risk patients with more aggressive transplantation strategies upfront, and can we define a group of patients who benefit from early allo-sct? How should novel therapies that demonstrate response in heavily pretreated patients be incorporated earlier in the treatment paradigm? Although the answers to these questions may improve outcomes, the most important aim should be to improve upfront cure rates. There can be no better salvage therapy than not needing it at all. No Our Approach to the Relapsed/Refractory HL Patient Given the multitude of reasonable therapeutic options for the relapsed or refractory HL patient, it is a challenge to identify the single best approach. We have diagrammed the general approach that we use for these patients (Fig. 1). We have omitted our approach to patients relapsing after ASCT because Crump recently diagrammed an approach to these patients that we agree with [37]. ACKNOWLEDGMENT Dr. Friedberg is a Clinical Scholar of the Leukemia and Lymphoma Society. AUTHOR CONTRIBUTIONS Conception/Design: Jason H. Mendler, Jonathan W. Friedberg Data analysis: Jason H. Mendler Manuscript writing: Jason H. Mendler, Jonathan W. Friedberg Final approval of manuscript: Jonathan W. Friedberg

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