Salvage Therapy in Hodgkin s Lymphoma. Duke University Medical Center, Durham, North Carolina, USA

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1 The Oncologist The Community Oncologist: Duke Oncology Fellows Series Salvage Therapy in Hodgkin s Lymphoma BRIAN J. BYRNE,JON P. GOCKERMAN Duke University Medical Center, Durham, North Carolina, USA Key Words. Hodgkin s disease Autologous transplant Salvage therapy Radiation therapy ABSTRACT Hodgkin s disease is a rare malignancy that affects approximately 7,500 patients per year in the U.S., leading to an estimated 1,400 deaths. The relapse rate for this disease varies from around 5% for early-stage disease to 35% for patients with advanced disease. Patients who relapse after chemotherapy have about a 20% cure rate with conventional salvage chemotherapy. Two randomized phase III studies have shown an improved failure-free survival rate with high-dose chemotherapy and autologous stem cell support compared with conventional chemotherapy in relapsed patients. They failed to show any improvement in CASE PRESENTATION Mr. T is a 50-year-old African-American male with a past medical history significant for type 2 diabetes mellitus. In January 2002, he presented to the emergency room with complaints of fever, chills, right groin pain, and a 25-pound weight loss over the last several months. Initial laboratory evaluation revealed an elevated white cell count of 11,800, hemoglobin of 11.7 g/dl, hematocrit of 35.8, platelet count of 406,000, and an elevated blood sugar of 516 mg/dl. A chest radiograph revealed right paratracheal lymphadenopathy and a patchy density overlying the left upper lung field. A computed tomography (CT) scan of the chest, abdomen, and pelvis showed enlarged lymph nodes in the mediastinum and the prevascular, right paratracheal, subcarinal, left axillary, left subclavian, azygoesophageal recess, and inguinal and bilateral iliac regions. A biopsy of the enlarged right cervical lymph node revealed fibrofatty connective overall survival. For patients who experience failure with autologous transplant, the options of single-agent chemotherapy with gemcitabine, vinblastine, or vinorelbine can be used for palliation. Standard myeloablative allogeneic bone marrow transplant has a high mortality rate in this population. Allogeneic transplant regimens with reduced intensity are currently being studied in clinical trials. Further studies on the use of monoclonal antibodies and radiolabeled antibodies need to be conducted to define their role in the treatment of Hodgkin s disease. The Oncologist 2007;12: tissue. A mediastinoscopy with biopsy was performed, and the pathology revealed mixed cellularity-type Hodgkin s lymphoma (Fig. 1). A gallium scan was positive in the mediastinal, left axillary, and right inguinal nodes. A bone marrow biopsy revealed Hodgkin s lymphoma, and the patient was considered to have clinical-stage IVB disease (Fig. 2). He underwent treatment with adriamycin, bleomycin, vincristine, and dacarbazine (ABVD) chemotherapy for four cycles. Restaging gallium scan was negative for nodal uptake, and a CT scan showed significant decrease in the lymphadenopathy. After four additional cycles of ABVD, repeat staging revealed new gallium-avid disease in the right paratracheal region, with stable disease upon CT scan. Repeat bone marrow biopsy was negative. The patient was considered to have refractory disease and underwent salvage therapy with rituximab, ifosfamide, carboplatin, and etoposide. After two cycles, he had a negative gallium Correspondence: Brian J. Byrne, M.D., Duke University Medical Center, Box 3841, Durham, North Carolina, USA. Telephone: ; Fax: ; byrne005@mc.duke.edu Received June 29, 2006; accepted for publication November 21, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 Byrne, Gockerman 157 Figure 1. Lymph node biopsy. (A): Diagnostic lymph node biopsy showing large cells surrounded by smaller lymphocytes. The patient was diagnosed with mixed cellularity-type Hodgkin s disease (hematoxylin and eosin stain, 100). (B): Lymph node biopsy using a stain for CD30. The brown staining cells are positive for CD30 and support the diagnosis of Hodgkin s disease (hematoxylin and eosin stain, 400). Figure 2. Bone marrow biopsy. (A): Patient s bone marrow showing replacement of the marrow with plasma cells, lymphocytes, and Hodgkin s disease (hematoxylin and eosin stain, 200). (B): Bone marrow biopsy stained with antibody to CD15. Image shows the marrow with CD15-positive cells (magnification, 200). scan. He then underwent autologous transplantation using cyclophosphamide, carmustine, and etoposide as a preparatory regimen. Two months after the autologous transplant, a gallium scan revealed interval development of gallium-avid disease within the superior mediastinum. CT scan revealed worsening adenopathy, and it was decided to treat him with radiation therapy. Restaging studies showed minimal improvement in the mediastinal adenopathy. Gallium scan revealed a mixed response to treatment, with decreased activity in the superior mediastinum but new activity in the right mid-lung zone, upper left posterolateral chest wall, and left lower quadrant. Due to pulmonary pneumonitis from the radiation therapy, Mr. T was observed and treated with steroids with improvement in his pulmonary toxicity. Repeat imaging 9 months later revealed unchanged lymphadenopathy but showed multiple low-attenuation lesions in the liver and spleen. Liver biopsy confirmed Hodgkin s disease (HD). He was initiated on single-agent vinblastine. Repeat imaging after four cycles of vinblastine showed increased porta hepatis and right axillary nodes. He was treated with gemcitabine, vinorelbine, and liposomal doxorubicin. After responding to this regimen, he was taken to a miniallogeneic transplant. He is currently being treated with prednisone and cyclosporine for graft-versus-host disease. Positron emission to-

3 158 Salvage Therapy in Hodgkin s Lymphoma mography (PET)/CT performed 6 months after the transplant shows PET-avid disease in the liver and increasing size of his lymph nodes. INTRODUCTION HD is a rare malignancy, and it is estimated that 7,350 patients in the U.S. will be diagnosed with it in 2006 [1]. HD is characterized by the presence of Reed Sternberg (RS) cells and their variants in an inflammatory background [2]. There is a bimodal peak in the incidence of HD, with most patients between the ages of 15 and 30 years, followed by another peak in adults over the age of 55 years [3]. Human immunodeficiency virus is the major risk factor for HD, with a risk 12 times greater than that for the general population [4]. Tremendous progress over the last several decades has been made in the treatment of HD. Advanced HD went from nearly a uniformly fatal disease to one with a 48% survival at 20 years with the advent of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy [5]. When ABVD was compared to MOPP, the 5-year failure-free survival rate increased from 50% to 61% [6]. There was no overall survival difference between the two regimens, and ABVD became the more commonly used regimen because of less shortand long-term toxicity. Even with multimodality therapy, including combination chemotherapy and radiation therapy, the relapse rate can vary from 5% for early-stage disease to 35% for advanced disease [6 8]. HD can still be fatal, and it is estimated that 1,410 patients will have died of this disease in 2006 [1]. PREDICTING RELAPSE AND IMPROVING THERAPY Because the best chance for cure lies with first-line therapy, efforts are underway to improve on ABVD while reducing toxicity from both chemotherapy and radiotherapy. ABVD was compared with MOPP/ABV in a multigroup clinical trial [9]. There was no difference in response rate, failurefree survival, and overall survival. However, MOPP/ABV caused more acute toxicity and a greater incidence of myelodysplastic syndrome (MDS) and acute leukemia. The authors concluded that ABVD was the superior regimen. Horning et al. [10] developed a 12-week chemotherapy regimen followed by 36 Gy of radiation to massive mediastinal disease, nodal disease greater than 5 cm, and macroscopic nodules in the intact spleen. In this pilot study of the Stanford V regimen, 72% of patients achieved a complete response with a failure-free survival rate of 87% at 2 years. In a controversial three-armed Italian study, 355 patients were randomly assigned to ABVD, Stanford V, or MOPP/epirubicin, bleomycin, vinblastine/cyclophosphamide, adriamycin, dexamethasone (MEC). The 5-year failure-free survival rate was 83% for ABVD, 85% for MEC, and only 67% for Stanford V [11]. However, radiation was not administered according to the Stanford protocol, calling into question the validity of these results. In a phase II U.K. study, the progression-free survival at 2 and 5 years for ABVD and Stanford V was identical [12]. A U.S. intergroup study is being conducted to compare Stanford V to ABVD. The German Hodgkin Lymphoma Study Group has conducted a series of trials in an attempt to optimize chemotherapy for advanced disease. In HD9, cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisone, vincristine, and bleomycin (BEACOPP) (Table 1) was compared with escalated BEACOPP versus COPP/ABVD [13]. Radiotherapy was given to all patients with an initial tumor size greater than 5 cm. The 5-year freedom-fromtreatment-failure (FFTF) rate was 67% for the COPP/ ABVD arm, 76% for BEACOPP, and 87% for escalated BEACOPP. A survival advantage was seen for escalated BEACOPP in patients with an International Prognostic Index of greater than 4. However, there was an increased risk of MDS, leukemia, and infertility with escalated BEA- COPP. Eleven patients with escalated BEACOPP developed acute myeloid leukemia compared with one in the COPP/ABVD arm. Efforts to reduce this risk, while still maintaining a high failure-free rate, were undertaken in HD12 [14]. Escalated BEACOPP 8 was compared with 4 cycles of escalated BEACOPP and 4 cycles of standard BEACOPP. The FFTF and overall survival at 2 years were similar between BEACOPP 4 and escalated BEA- COPP 4 (88% and 94%) and escalated BEACOPP 8 (90% vs. 96%). The European Organisation for Research and Treatment of Cancer is comparing combination BEA- COPP to ABVD in a clinical trial. The use of PET scans to predict response to chemotherapy in patients with advanced disease is being explored. Gallamini et al. [17] prospectively studied 108 patients to determine whether a PET scan can predict treatment outcome in advanced-stage HD. All patients underwent a PET scan after two cycles of chemotherapy, and recurrences were confirmed by biopsy. After two cycles of chemotherapy, 20 patients had a positive PET scan. The progressionfree survival for patients with PET positivity was 13% at 18 months compared with 96% for patients with a negative scan. The hazard ratio for a positive PET scan was Further studies evaluating the use of PET to change treatment courses are being planned. For instance, in HD15, a study currently being conducted by the German Hodgkin Lymphoma Study Group, involved-field radiotherapy is being used only for patients with PET-positive disease of more than 2.5 cm after 6 8 cycles of chemotherapy [14].

4 Byrne, Gockerman 159 Table 1. First-line chemotherapy regimens for Hodgkin s disease Regimen/reference Chemotherapy ABVD [15] 25 mg/m 2 doxorubicin; days 1, U/m 2 bleomycin; days 1, 15 6 mg/m 2 vinblastine; days 1, mg/m 2 dacarbazine; days 1, 15 BEACOPP [13] 650 mg/m 2 cyclophosphamide; day 1 25 mg/m 2 doxorubicin; day mg/m 2 etoposide; days mg/m 2 procarbazine; days mg/m 2 prednisone; days mg/m 2 vincristine (2-mg maximum); day 8 10 U/m 2 bleomycin; day 8 Escalated BEACOPP [13] 1200 mg/m 2 cyclophosphamide; day 1 35 mg/m 2 doxorubicin; day mg/m 2 etoposide; days mg/m 2 procarbazine; days mg/m 2 prednisone; days mg/m 2 vincristine (2-mg maximum); day 8 10 U/m 2 bleomycin; day 8 G-CSF from day 8 MOPP [16] 6 mg/m 2 mechlorethamine; days 1, mg/m 2 vincristine; days 1, mg/m 2 procarbazine daily; days mg/m 2 prednisone; days 1 14 Stanford V [10] Weeks 1, 3, 5, 7, 9, and mg/m 2 doxorubicin 6 mg/m 2 vinblastine 6 mg/m 2 mechlorethamine; weeks 1, 5, and 9 only Weeks 2, 4, 6, 8, 10, and mg/m 2 vincristine (2-mg maximum) 5 U/m 2 bleomycin Weeks 3, 7, and 11 for 2 consecutive days 60 mg/m 2 etoposide Weeks mg/m 2 prednisone every other day for 10 weeks and then tapered by 10 mg every other day; followed by consolidative irradiation Abbreviation: G-CSF, granulocyte cell-stimulating factor. RELAPSE FROM CHEMOTHERAPY Patients who either are refractory to or relapse after initial combination chemotherapy have around a 20% chance of cure with conventional second-line regimens [18]. Longo et al. [18] retrospectively analyzed 107 relapsed patients. Ninety-four were treated with MOPP as their backbone regimen, whereas 13 were treated with MOPP/ABVD. Half of these relapses occurred within 1 year of completing treatment, whereas less than 10% of relapses occurred 5 years after chemotherapy. The timing of the relapse helped to predict response to second-line conventional therapy. For patients who were refractory (defined as failure to obtain a complete response), the median overall survival was only 16 months. If the time of relapse was within 1 year of obtaining a complete response, 49% achieved a second complete response. These remissions were not durable, and at 5

5 160 Salvage Therapy in Hodgkin s Lymphoma years, only 14% were disease-free. The median overall survival was 2.6 years for this group as a whole. This is in contrast to patients whose first complete remission lasted more than 12 months. Seventy-nine percent of patients achieved a second complete response. There were prolonged responses, and the actuarial disease-free survival at 21 years was 45%. The overall survival for this group as a whole was 4.3 years. The importance of obtaining an initial complete response was shown in additional studies. In another series of 115 patients, no one refractory to primary treatment was disease-free at 3 years [19]. Lohri et al. [20] conducted a retrospective analysis of 71 patients treated with curative intent in first relapse. Sixteen patients received high-dose therapy with stem cell support, whereas the remaining patients were treated with MOPP, ABVD, or extended-field radiation. Three risk factors (i.e., stage IV disease at diagnosis, B symptoms at relapse, and a short time to relapse) predicted prolonged response to second-line therapy. If one risk factor was present, the failurefree survival at 5 years was 17% compared with 82% for patients with no risk factors. AUTOLOGOUS TRANSPLANTATION Because of the poor overall survival in patients with relapsed HD, the use of autologous bone marrow transplantation has been explored. Early studies using autologous bone marrow transplantation in patients with refractory or relapsed HD produced complete response rates of 48% 69% [21 24]. Prolonged disease-free survivals were obtained. In two of the studies, 27% of patients were without disease at approximately 4 years. The treatment-related mortality was high, ranging from 4% to 23%. Several advances in supportive care and the use of peripheral-blood progenitor cells during an autologous transplant has subsequently reduced the treatment-related mortality to less than 3% [25]. Because of these promising early studies, highdose chemotherapy with autologous transplantation was then compared to conventional chemotherapy in two phase III randomized trials [26, 27]. The British National Lymphoma Investigation group designed a phase III trial to show a 30% improvement in survival with transplant at 5 years [26]. Sixty-six patients were needed, but the study closed early due to poor enrollment. During the second half of the study, patients refused randomization and demanded to undergo an autologous transplant. Therefore, 40 patients were randomized to carmustine, etoposide, cytarabine, and melphalan (BEAM) plus autologous transplant versus the same drugs at lower doses (mini-beam) [26]. Eligibility criteria included patients who failed to achieve a complete response with MOPP or a similar regimen, had high-grade histology, relapsed within a year, or had two or more relapses. Twenty patients were enrolled into each arm. At 3 months, there was no significant difference in overall response rate (74% for BEAM and 60% for mini-beam). The treatment-related mortality was 10% in the BEAM arm. At 3 years, the overall event-free survival was significantly higher in the BEAM arm (53%) compared with the mini-beam arm (10%). However, the study failed to show any statistically significant overall survival advantage. The German Hodgkin Lymphoma Study Group [27] conducted a phase III trial with 161 patients who had relapsed from initial chemotherapy. After two cycles of dexamethasone plus BEAM chemotherapy (Dexa-BEAM), 81% of patients experienced disease response. These patients were then randomized to two additional cycles of Dexa-BEAM or autologous stem cell transplant using BEAM as the preparatory regimen. At 3 years, the FFTF for patients who were responsive to the first two cycles was 34% for Dexa-BEAM alone compared with 55% in the transplant arm. When patients were stratified for early relapse (relapse within the first 12 months), the FFTF was 41% for autologous transplant versus 12% for conventional therapy. For patients with late relapse, there was also a significant difference in FFTF favoring the autologous transplant arm (75% vs. 44%). There was no difference in overall survival. These two randomized trials support the use of autologous transplant as second-line therapy by showing an improved disease-free survival. The authors tried to explain the lack of a survival advantage. Reasons offered for no improvement in survival included the fact that almost half of the patients in the no-transplant arm received a transplant in subsequent relapses, and multiple remissions, although not sustained, could be obtained with conventional therapy [27]. Another reason was that 40% 50% of patients who undergo an autologous transplant will subsequently relapse. Moskowitz et al. [28] developed a prognostic model based on 65 consecutively treated patients with relapsed or refractory HD to predict the outcome from an autologous transplant. Three factors (i.e., extranodal sites of disease, complete response of less than 1-year duration or primary refractory disease, and B symptoms) predicted event-free survival. For patients with zero or one factor, the 5-year event-free and overall survivals were 83% and 90%, respectively. If two factors were present, the 5-year eventfree and overall survivals were 27% and 57%, respectively, and this decreased to 10% and 25%, respectively, if all factors were present. In a study conducted by Stanford University [29], B symptoms, stage IV disease involving the bone marrow or lung, and greater-than-minimal residual disease

6 Byrne, Gockerman 161 at the time of presentation for transplantation were associated with a poor prognosis. The 3-year failure-from-progression was 85%, 57%, 41%, and 20% for zero, one, two, and three factors, respectively. The most important clinical factor for long-term survival after stem cell transplantation is duration of prior complete response. In an abstract from the American Society of Clinical Oncology in 2006 [30], a retrospective chart review of 115 patients who underwent autologous transplantation was conducted. The 5-year survival of patients with a complete response to chemotherapy lasting greater than 12 months was 63%. This was statistically significantly higher than the 44% 5-year survival in patients whose CR was less than 12 months. Moskowitz et al. [31] analyzed the effect of chemosensitive disease before transplantation in patients with biopsyproven refractory HD. Chemosensitive disease was defined in this article as a greater than 25% response to the ifosfamide, carboplatin, and etoposide regimen. For this group of 75 patients, the actuarial 10-year progression-free survival and overall survival were 45% and 48%, respectively. The overall survival for patients with chemosensitive disease at 10 years was 66% compared with 17% for those with chemoresistant disease. The authors concluded that autologous transplantation should be offered to patients with refractory disease who are chemosensitive to a second-line regimen. This result was also found in a retrospective review from Royal Marsden Hospital involving 199 patients who underwent an autologous transplant for relapsed and refractory HD [32]. For patients with chemotherapy-resistant disease, the hazard ratio for decreased progression-free survival was 3.5 (95% confidence interval, ), and for overall survival, it was 4.4 (95% confidence interval, ). These studies show the importance of cytoreduction before autologous transplantation in effecting prognostic outcome. To date, there has been no randomized study comparing regimens for cytoreduction before autologous transplantation. Most of these studies are small, and many of the regimens are similar. Table 2 summarizes the phase II data for various treatment regimens with more than 20 patients in the relapsed or refractory setting. In conclusion, autologous transplantation for HD has been shown to improve progression-free survival in phase III trials. It has not been shown to improve overall survival. Patients with chemosensitive disease before transplantation have improved outcomes. The time from complete response to relapse is an important prognostic factor, with a long disease-free interval resulting in improved survival. Issues still under study include the incorporation of radiation into the treatment regimen and the ideal chemotherapy regimen before transplantation. SINGLE-AGENT THERAPY For patients who relapse after or are ineligible for autologous transplantation, gemcitabine, vinblastine, and vinorelbine are agents that have efficacy for palliation. Gemcitabine is a pyrimidine antimetabolite with a broad range of efficacy in solid tumors and non-hodgkin s lymphoma [50]. In a phase II study, 23 patients with relapsing or refractory HD were treated with gemcitabine at a dose of 1,250 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. Patients with a previous autologous or allogeneic transplant were excluded. Two patients (9%) achieved a complete response, and the overall response rate was 39%. The duration of remission was 6.7 months for partial responders and 14 months (2 months and 22 months) for the complete responders [50]. Venkatesh et al. [51] conducted a study on 29 patients with HD, of whom 18 had relapsed after autologous stem cell transplantation. Gemcitabine was given at a dose of 1,250 mg/m 2 on days 1, 8, and 15 but had to be reduced secondary to toxicity to 1,000 mg/m 2 on days 1 and 8. The partial response rate was 22%, with a median time-toprogression of 6.4 months. The overall survival for this trial was 26.9 months. Two additional trials have produced response rates of 43% and 64% [52, 53]. These trials confirm the role of gemcitabine as a palliative agent in patients with highly refractory or relapsed HD [51 53]. Vinblastine, a vinca alkaloid, is a highly effective agent for patients with HD. Early studies have shown a response rate of 90% and a cure rate of 10% when it is used as singleagent front-line therapy [54]. It has also been studied in the relapsed setting at the National Cancer Institute in 17 patients who experienced treatment failure with autologous transplantation [55]. Patients initially received vinblastine at doses of 4 6 mg/m 2 every 1 2 weeks until disease progression. The overall response rate was 59% (10 patients), with two patients achieving a complete response. The patients who responded received a median of eight doses of vinblastine in combination regimens before its use as a single agent. The median event-free and overall survivals were 8.3 months and 38.8 months, respectively. The two complete responders remained in remission and continued receiving vinblastine for more than 4.6 and 9 years at the time the manuscript was written. Vinorelbine, a semisynthetic vinca alkaloid, has also been studied as a single agent. Twenty-four heavily pretreated patients underwent weekly infusions at a dose of 30 mg/m 2 [56]. The objective response rate was 50%, with a median duration of response of 6 months. The regimen was well tolerated, and the peripheral neuropathy was mild. In a second study, 25 mg/m 2 vinorelbine was given on days 1 and 8 of a 3-week cycle to eight patients, four of whom underwent a prior autologous

7 162 Salvage Therapy in Hodgkin s Lymphoma Table 2. Salvage Chemotherapy Regimens Reference Regimen Chemotherapeutic drugs No. of patients RR (%) CR (%) Treatmentrelated deaths Aparicio et al. [33] ESHAP Methylprednisolone Cytarabine Cisplatin Aviles et al. [34] Modified Stanford V Epirubicin Vinblastine Cyclophosphamide Vincristine Bleomycin Prednisone Baetz et al. [35] GDP Gemcitabine Dexamethasone Cisplatin Bonfante et al. [36] Vinorelbine Ifosfamide Colwill et al. [37] Mini-BEAM BCNU Cytarabine Melphalan Enblad et al. [38] MIME Methyl-gag Ifosfamide Methotrexate Ferme et al. [39] MINE Mitoguazone Ifosfamide Vinorelbine Fernandez-Jimenez et al. [40] Mini-BEAM BCNU Cytarabine Melphalan Jackson et al. [41] IEE Ifosfamide Epirubicin Josting et al. [42] DHAP Dexamethasone High-dose cytarabine Cisplatinum Moskowitz et al. [28] ICE Ifosfamide Carboplatin Cyclophosphamide (Continued)

8 Byrne, Gockerman 163 Table 2. (Continued) Reference Regimen Chemotherapeutic drugs No. of patients RR (%) CR (%) Treatmentrelated deaths Moskowitz et al. [28] ICE Ifosfamide Carboplatin Cyclophosphamide Oyan et al. [43] IIVP Ifosfamide Idarubicin Proctor et al. [44] IVE Ifosfamide Epirubicin Ribrag et al. [45] VIP Ifosfamide Cisplatin Rodriguez et al. [46] ASHAP Adriamycin Methylprednisone Cytarabine Cisplatin Schmitz et al. [27] Dexa-BEAM Dexamethasone % Carmustine Cytarabine Melphalan Szanto, Fleischmann, Eckhardt [47] CEP CCNU Prednimustine Walewski et al. [48] CN3OP Mitoxantrone Cyclophosphamide Vincristine Prednisone Wiernik et al. [49] MVC Mitoxantrone Vinblastine CCNU Abbreviations: BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea; CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CR, complete response; RR, response rate. transplant [57]. The overall response rate was 50%, and one patient with primary refractory HD responded to therapy. SALVAGE RADIATION THERAPY Leigh et al. [58] reported on 28 patients treated with salvage radiation therapy after they experienced treatment failure with combination chemotherapy. After receiving either total nodal irradiation in 64% or mantle-field radiation in 29%, the complete response rate was 93%. The median relapse-free survival was 46 months, and the 5-year actuarial relapse-free rate was 40%. Campbell et al. [59] reported on 81 patients treated with salvage radiation after experiencing treatment failure with at least one prior chemotherapy regimen. Each patient was treated with a planned dose of 30 Gy with or without salvage chemotherapy. Seven percent of patients had received previous radiation therapy, whereas 4% had relapsed after high-dose chemotherapy. The complete response rate was 75%, with an actuarial median failure-free survival time of

9 164 Salvage Therapy in Hodgkin s Lymphoma 2.6 years. At 5 years, 35.9% of patients were disease-free. The complete response rate was lower for patients with stage III or IV disease (47%) versus stage I or II (80%). In addition, duration of complete response to prior chemotherapy was predictive of a response to radiation. In patients refractory to the prior chemotherapeutic regimen, 61% had a CR compared with 89% for a response duration of less than 12 months and 94% for a response duration of greater than 12 months. Predictive factors for freedom-from-progression after multivariate analysis were age 50 years, no B symptoms at relapse, CR to previous chemotherapy, and lack of extranodal disease. The German Hodgkin Lymphoma Study Group [60] reported on 100 patients treated with salvage radiotherapy at the time of first relapse. In this group, seven patients were initially treated with radiation alone, and 61 were treated with combined chemotherapy and radiation. The remaining 32 patients were treated with chemotherapy alone. For salvage radiotherapy, 42% received mantle-field irradiation, 12% total or subtotal nodal irradiation, 8% inverted Y-field irradiation, and 37% involved-field irradiation. The complete response rate was 77%. Of the complete responders, 88% had stage I/II disease, whereas only12% had stage III/IV disease at the time of relapse. The actuarial 5-year failure-free and overall survivals were 28% and 51%, respectively. Prognostic factors that affected survival were stage at treatment, presence of B symptoms, Karnofsky status, and duration of initial response. Patients enrolled in these studies are a highly selected patient population. For instance, in the study from Josting et al. [60], only 100 patients (approximately 2%) eventually underwent this treatment approach out of 4,754 patients enrolled in the German Hodgkin Lymphoma Study Group trials HD4 HD9. These studies suggest that patients who have early-stage disease with no extranodal sites of involvement, lack of B symptoms, and a good response to first-line therapy are the best candidates for this approach. ALLOGENEIC TRANSPLANTATION The use of myeloablative allogeneic bone marrow transplantation for patients with relapsed or refractory HD is highly controversial. There is a high treatment-related mortality and low progression-free survival rate [61 63]. Between 1982 and 1992, 100 patients underwent a human leukocyte antigen-identical sibling bone marrow transplant with results reported to the International Bone Marrow Transplant Registry. The treatment-related mortality from the procedure was unacceptably high at 61%. The 3-year overall survival was 21%, with a disease-free survival of only 15% [61]. In a review by Akpek et al. [63] from Johns Hopkins University, 53 patients underwent an allogeneic transplant. The treatment-related mortality was 43%. There were long-term survivors, and at 10 years, the event-free survival was 26%, with an overall survival of 30%. Milpeid et al. [62] performed a case control series comparing 45 patients who underwent an allogeneic transplant to matched cases who received an autologous transplant. The treatment-related mortality of 31% in patients who underwent an allogeneic transplant was higher than the 18% mortality of those treated with an autologous transplant. The 4-year progression-free survival from a myeloablative allogeneic transplant was only 15%. When allogeneic was compared with autologous transplantation, there was no difference in relapse rate rates at 4 years, and there was a trend toward improved overall survival at 4 years (37% vs. 25%; p.074) with an autologous transplant. Because of this high treatment-related mortality, studies using reduced-intensity regimens are being conducted in patients with multiple relapses of HD. Anderlini et al. [64] reported on 40 heavily pretreated patients who underwent a reduced-intensity regimen. The median number of prior chemotherapy regimens was five, with 75% of patients having undergone a prior autologous transplant. The 100-day treatment mortality was 5%, with a cumulative incidence of 22% at 18 months. Overall survival at 18 months was 61%, with a progression-free survival rate of 32% at 18 months. Peggs et al. [65] reported on 49 patients who underwent a reduced-intensity allogeneic transplant. Most patients, 90%, underwent a previous autologous transplant. The treatment-related mortality was 16.3% at 730 days. The 4-year overall survival was 55.7%, with a progression-free survival of 39%. This approach is still being studied, and it remains to be seen whether these responses are durable and potentially curative. ANTIBODY THERAPY CD30 is normally expressed on activated B, T, and natural killer cells [66]. It is also highly expressed on the Reed Sternberg cells. Thus, CD30 seems to be an ideal target for the treatment of HD. SGN-30, an antibody to CD30, was found to inhibit the growth of Hodgkin s cell lines in vitro and prolong the survival of severe-combined immunodeficiency mice in vivo. SGN-30 was then developed for study in humans, with disappointing clinical results. In a phase II study, 15 patients, 73% of whom experienced disease progression after transplantation, were treated with six weekly intravenous doses of SGN-30 [67]. There were no objective responses, and only six patients had stable disease. MDX-060, a fully human anti-cd30 immunoglobulin G1k monoclonal antibody, has been studied in 40 patients with HD in a phase I/II study. The results were disappointing, with one complete response and two partial responses,

10 Byrne, Gockerman 165 for an overall response rate of only 7.5%. Thus, with the current state of knowledge, these agents have a minimal role in the treatment of HD. The use of a radiolabeled iodine-131 murine CD30 monoclonal antibody has been reported in 22 patients [68]. One patient had a complete response that lasted for 5 months; 5 of the 22 had a partial response, with the longest duration being 6 months. Grade 4 hematotoxicity was experienced in 33% of patients. Further studies need to be conducted to determine whether there is a role for this antibody in the treatment of HD. About 25% of Reed Sternberg cells express CD20 on their cell surface [69]. It is also postulated the surrounding B lymphocytes, which express CD20, may contribute to the survival of the Reed Sternberg cells. Therefore, rituximab may have a role in HD by removing the supporting B cells. This theory was tested in a pilot study in which 22 patients REFERENCES 1 Jemal A, Siegel R, Ward E et al. Cancer statistics, CA Cancer J Clin 2006;56: Harris NL. Hodgkin s disease: Classification and differential diagnosis. Mod Pathol 1999;12: Ekstrand BC, Horning SJ. Hodgkin s disease. Blood Rev 2002;16: Engels EA, Goedert JJ. Human immunodeficiency virus/acquired immunodeficiency syndrome and cancer: Past, present, and future. J Natl Cancer Inst 2005;97: Longo DL, Young RC, Wesley M et al. Twenty years of MOPP therapy for Hodgkin s disease. J Clin Oncol 1986;4: Canellos GP, Anderson JR, Propert KJ et al. Chemotherapy of advanced Hodgkin s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327: Meyer RM, Gospodarowicz MK, Connors JM et al. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin s lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23: Kuppers R, Yahalom J, Josting A. Advances in biology, diagnostics, and treatment of Hodgkin s disease. Biol Blood Marrow Transplant 2006; 12(suppl 1): Duggan DB, Petroni GR, Johnson JL et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin s disease: Report of an intergroup trial. J Clin Oncol 2003;21: Horning SJ, Williams J, Bartlett NL et al. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin s disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 2000;18: Federico M, Levis A, Luminari S et al. ABVD vs. STANFORD V (SV) vs. MOPP-EBV-CAD (MEC) in advanced Hodgkin s lymphoma. Final results of the IIL HD9601 randomized trial. J Clin Oncol 2004;22(suppl): Johnson P, Hoskin P, Horwich A et al. Stanford V (SV) regimen versus ABVD received rituximab at a dose of 375 mg/m 2 weekly for 6 weeks. The median number of prior regimens was four, with 82% of patients undergoing a prior autologous stem cell transplant. One patient had a complete response, and four had a partial response, for a response rate of 22%. The median duration of response was 7.8 months. Responses were limited to patients with nodal or splenic involvement. There were no responses in extranodal sites. For patients whose Reed Sternberg cells express CD20, the response rate was 33% compared with 19% in those who did not. The authors concluded that rituximab may have a role in the treatment of HD, but further studies are needed. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST The authors indicate no potential conflicts of interest. for the treatment of advanced Hodgkin lymphoma (HL): Results of a UK NCRI/LTO randomised phase II trial. Proc Am Soc Hematol 2004;104: Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin s disease. N Engl J Med 2003;348: Diehl V, Behringer K. Could BEACOPP be the new standard for the treatment of advanced Hodgkin s lymphoma? Cancer Invest 2006;24: Bonadonna G, Santoro A. ABVD chemotherapy in the treatment of Hodgkin s disease. Cancer Treat Rev 1982;9: Devita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin s disease. Ann Intern Med 1970;73: Gallamini A, Rigacci L, Merli F et al. The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin s disease. Haematologica 2006;91: Longo DL, Duffey PL, Young RC et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin s disease after combination chemotherapy: The low probability for cure. J Clin Oncol 1992;10: Bonfante V, Santoro A, Viviani S et al. Outcome of patients with Hodgkin s disease failing after primary MOPP-ABVD. J Clin Oncol 1997;15: Lohri A, Barnett M, Fairey RN et al. Outcome of treatment of first relapse of Hodgkin s disease after primary chemotherapy: Identification of risk factors from the British Columbia experience 1970 to Blood 1991; 77: Armitage JO, Bierman PJ, Vose JM et al. Autologous bone marrow transplantation for patients with relapsed Hodgkin s disease. Am J Med 1991; 91: Carella AM, Congiu AM, Gaozza E et al. High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin s disease patients: An Italian study group report. J Clin Oncol 1988;6: Jagannath S, Dicke KA, Armitage JO et al. High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin s disease. Ann Intern Med 1986;104:

11 166 Salvage Therapy in Hodgkin s Lymphoma 24 Phillips GL, Wolff SN, Herzig RH et al. Treatment of progressive Hodgkin s disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 1989;73: Moskowitz C. An update on the management of relapsed and primary refractory Hodgkin s disease. Semin Oncol 2004;31(suppl): Linch DC, Winfield D, Goldstone AH et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin s disease: Results of a BNLI randomised trial. Lancet 1993;341: Schmitz N, Pfistner B, Sextro M et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin s disease: A randomised trial. Lancet 2002;359: Moskowitz CH, Nimer SD, Zelenetz AD et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: Analysis by intent to treat and development of a prognostic model. Blood 2001;97: Horning SJ, Chao NJ, Negrin RS et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin s disease: Analysis of the Stanford University results and prognostic indices. Blood 1997;89: Holland DW, Engelhardt BG, Goodman SA et al. High dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin s Lymphoma. J Clin Oncol 2006;24(suppl): Moskowitz CH, Kewalramani T, Nimer SD et al. Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin s disease. Br J Haematol 2004;124: Sirohi B, Cunningham D, Norman RA et al. Long-term outcome of highdose chemotherapy and autologous stem cell transplantation in relapsed/ refractory Hodgkin s disease: A cohort of 199 pts from Royal Mardsen Hospital. J Clin Oncol 2006;24(suppl): Aparicio J, Segura A, Garcera S et al. ESHAP is an active regimen for relapsing Hodgkin s disease. Ann Oncol 1999;10: Aviles A, Neri N, Garcia EL et al. Treatment of refractory Hodgkin s disease with modified Stanford V program. Med Oncol 2001;18: Baetz T, Belch A, Couban S et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin s disease: A phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 2003;14: Bonfante V, Viviani S, Devizzi L et al. High-dose ifosfamide and vinorelbine as salvage therapy for relapsed or refractory Hodgkin s disease. Eur J Haematol 2001;64(suppl): Colwill R, Crump M, Couture F et al. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin s disease before intensive therapy and autologous bone marrow transplantation. J Clin Oncol 1995;13: Enblad G, Hagberg H, Gustavsson A et al. Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for Hodgkin s disease: A prospective study. Eur J Haematol 1998;60: Ferme C, Bastion Y, Lepage E et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin s disease. Ann Oncol 1995;6: Fernandez-Jimenez MC, Canales MA, Ojeda E et al. Salvage chemotherapy with mini-beam for relapsed or refractory Hodgkin s disease prior to autologous peripheral blood stem cell transplantation. Haematologica 1999;84: Jackson GH, Angus B, Carey PJ et al. High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin s disease: A report on toxicity and efficacy. Leuk Lymphoma 2000;37: Josting A, Rudolph C, Reiser M et al. Time-intensified dexamethasone/ cisplatin/cytarabine: An effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin s disease. Ann Oncol 2002;13: Oyan B, Koc Y, Ozdemir E et al. Ifosfamide, idarubicin, and etoposide in relapsed/refractory Hodgkin disease or non-hodgkin lymphoma: A salvage regimen with high response rates before autologous stem cell transplantation. Biol Blood Marrow Transplant 2005;11: Proctor SJ, Taylor PR, Angus B et al. High-dose ifosfamide in combination with etoposide and epirubicin (IVE) in the treatment of relapsed/refractory Hodgkin s disease and non-hodgkin s lymphoma: A report on toxicity and efficacy. Eur J Haematol 2001;64(suppl): Ribrag V, Nasr F, Bouhris JH et al. VIP (etoposide, ifosfamide and cisplatinum) as a salvage intensification program in relapsed or refractory Hodgkin s disease. Bone Marrow Transplant 1998;21: Rodriguez J, Rodriguez MA, Fayad L et al. ASHAP: A regimen for cytoreduction of refractory or recurrent Hodgkin s disease. Blood 1999;93: Szanto I, Fleischmann T, Eckhardt S. Treatment of resistant Hodgkin s disease with CCNU, etoposide and prednimustine (CEP). Oncology 1991;48: Walewski J, Krzyzanowska JB, Kraszewska E et al. CN3OP: An active regimen in patients with relapsed/refractory Hodgkin s lymphoma. Med Oncol 2000;17: Wiernik PH, Dutcher JP, Einzig AI et al. Mitoxantrone, vinblastine, and lomustine (CCNU) (MVC): A highly active regimen for advanced and poor-prognosis Hodgkin s disease. Cancer J Sci Am 1998;4: Santoro A, Bredenfeld H, Devizzi L et al. Gemcitabine in the treatment of refractory Hodgkin s disease: Results of a multicenter phase II study. J Clin Oncol 2000;18: Venkatesh H, Di Bella N, Flynn TP et al. Results of a phase II multicenter trial of single-agent gemcitabine in patients with relapsed or chemotherapyrefractory Hodgkin s lymphoma. Clin Lymphoma 2004;5: Zinzani PL, Bendandi M, Stefoni V et al. Value of gemcitabine treatment in heavily pretreated Hodgkin s disease patients. Haematologica 2000;85: Aurer I, Radman I, Nemet D et al. Gemcitabine in the treatment of relapsed and refractory Hodgkin s disease. Onkologie 2005;28: Carter SK, Livingston RB. Single-agent therapy for Hodgkin s disease. Arch Intern Med 1973;131: Little R, Wittes RE, Longo DL et al. Vinblastine for recurrent Hodgkin s disease following autologous bone marrow transplant. J Clin Oncol 1998; 16: Devizzi L, Santoro A, Bonfante V et al. Vinorelbine: An active drug for the management of patients with heavily pretreated Hodgkin s disease. Ann Oncol 1994;5: Rule S, Tighe M, Davies S et al. Vinorelbine in the treatment of lymphoma. Hematol Oncol 1998;16: Leigh BR, Fox KA, Mack CF et al. Radiation therapy salvage of Hodgkin s disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 1993; 27: Campbell B, Wirth A, Milner A et al. Long-term follow-up of salvage radiotherapy in Hodgkin s lymphoma after chemotherapy failure. Int J Radiat Oncol Biol Phys 2005;63: Josting A, Nogova L, Franklin J et al. Salvage radiotherapy in patients with

12 Byrne, Gockerman 167 relapsed and refractory Hodgkin s lymphoma: A retrospective analysis from the German Hodgkin Lymphoma Study Group. J Clin Oncol 2005; 23: Gajewski JL, Phillips GL, Sobocinski KA et al. Bone marrow transplants from HLA-identical siblings in advanced Hodgkin s disease. J Clin Oncol 1996;14: Milpied N, Fielding AK, Pearce RM et al. Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin s disease. European Group for Blood and Bone Marrow Transplantation. J Clin Oncol 1996;14: Akpek G, Ambinder RF, Piantadosi S et al. Long-term results of blood and marrow transplantation for Hodgkin s lymphoma. J Clin Oncol 2001;19: Anderlini P, Saliba R, Acholonu S et al. Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin s disease: Low transplant-related mortality and impact of intensity of conditioning regimen. Bone Marrow Transplant 2005;35: Peggs KS, Hunter A, Chopra R et al. Clinical evidence of a graft-versus- Hodgkin s-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet 2005;365: Wahl AF, Klussman K, Thompson JD et al. The anti-cd30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin s disease. Cancer Res 2002;62: Leonard JP, Rosenblatt JD, Bartlett NL et al. Phase II study of SGN-30 (anti-cd 30n monoclonal antibody) in patients with refractory or recurrent Hodgkin s disease. Blood 2004;104: Schnell R, Dietlein M, Staak JO et al. Treatment of refractory Hodgkin s lymphoma patients with an iodine-131-labeled murine anti-cd30 monoclonal antibody. J Clin Oncol 2005;23: Younes A, Romaguera J, Hagemeister F et al. A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer 2003;98: