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HISTORICAL PERSPECTIVE
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Hodgkin lymphoma first became a curable neoplasm through the systematic study of the spread of the disease and the use of higher dose, extended field radiotherapy delivered with supervoltage techniques.137 When used alone, radiotherapy doses to involved fields usually ranged from 3500 to 4400 cGy with prophylactic doses of 3000 to 3500 cGy to uninvolved tissues. The mantle, paraaortic region, and pelvis constitute the classic radiotherapy regions. With increased recognition of late effects, radiation therapy has been modified to reduce field size to areas of known or bulky disease and doses have been lowered, coincident with addition of systemic chemotherapy. Furthermore, initial disease reduction with chemotherapy results in less radiation exposure to the neck, female breast, heart, and lungs, all of which are anticipated to result in fewer late complications. Advances in radiotherapy techniques deliver more precise dose distributions, sparing normal tissues. The first modern combination chemotherapy program was the MOPP regimen devised by Devita and colleagues.22 The national mortality figures for cHL decreased by more than 60 percent in the decade that followed the introduction of MOPP.138 Bonadonna and colleagues developed an important alternative regimen for the treatment of cHL. ABVD, which was effective in the treatment of patients who had failed MOPP139,140 and offered a more favorable toxicity profile. ABVD subsequently became the preferred primary chemotherapy regimen, alone or in combination with radiotherapy.141,142 Of the multiple alternative chemotherapy regimens introduced for the treatment of advanced cHL, only the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine (BEACOPP) combination developed by Diehl and colleagues has demonstrated superior cure rates in multiple phase III studies.143,144 Table 97–3 describes the drugs, doses, and schedules of combination chemotherapy programs effective in the management of Hodgkin lymphoma.
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FAVORABLE, LIMITED-STAGE DISEASE
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Favorable, limited-stage Hodgkin lymphoma is typically defined in North America as asymptomatic stage I or II supradiaphragmatic disease with no bulky sites. A more restrictive definition is used in Europe based on the number of Ann Arbor sites, ESR, age and extranodal sites, as well as bulky disease (Table 97–4).143 Approximately 35 percent of stages I and II patients meet this more limited definition of favorable disease. For many years, extended-field (subtotal lymphoid) radiotherapy administered after staging laparotomy, was the treatment of choice for early stage, favorable Hodgkin lymphoma. A change in that standard was compelled by the observation that the overall mortality rate from other causes, particularly second cancers, exceeded deaths resulting from Hodgkin lymphoma at 15 to 20 years.145 Early studies from Stanford University demonstrated that involved-field radiotherapy plus chemotherapy produced results equivalent or superior to wide-field radiotherapy.146 Subsequently, several randomized trials demonstrated the superiority of involved-field radiotherapy plus anthracycline-containing chemotherapy compared to extended-field radiotherapy in early stage favorable Hodgkin lymphoma.147,148
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The next series of clinical trials were designed to test the optimal number of cycles of chemotherapy and the volume and dose of radiotherapy when both modalities are used in limited Hodgkin lymphoma. The Milan Tumor Institute documented disease control in more than 95 percent of early stage cHL patients treated with four cycles of ABVD and radiotherapy, with no advantage seen for extended- field radiotherapy compared to involved-field radiotherapy.149 Similarly, no advantage to more extensive radiation in combination with chemotherapy was observed in a German Hodgkin Study Group (GHSG) study.150 A comparison of two versus four cycles of ABVD chemotherapy paired with 20 Gy or 30 Gy radiotherapy was made in a four-arm trial conducted by the GHSG, evaluating patients with “favorable” early stage cHL, defined as patients with two or fewer sites of disease, no masses larger than 10 cm, a normal ESR, and no extranodal sites of disease. This trial produced equivalent outstanding outcomes for all four arms, with 91 to 93 percent freedom from treatment failure after 5 years, and established two cycles of ABVD followed by 20 Gy of involved field radiotherapy as a new standard of care for early stage, favorable cHL. In a subsequent study, the GHSG evaluated eliminating drugs from the ABVD regimen, randomizing patients between four cycles of ABVD, AV, ABV, or AVD plus 30 Gy involved-field radiotherapy. The AV and ABV arms were closed early because of clearly inferior outcomes, and subsequent analysis suggests that the AVD arm is also worse than the full four-drug combination.151
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The high cure rate with current limited chemotherapy and low-dose radiotherapy creates a high standard for comparison with alternative treatment approaches. Nevertheless, considerable interest exists in devising management strategies omitting radiotherapy altogether, largely motivated by desires to avoid secondary malignancies and late cardiopulmonary complications.145 This approach is particularly favored for women younger than age 30 years, who have a very high risk of developing breast cancer if treated with mediastinal radiotherapy.145,152 Canellos and colleagues treated 71 patients with early stage, favorable cHL with six cycles of ABVD without radiotherapy and achieved a 5-year failure-free survival of 92 percent.153 A single institution study of ABVD versus ABVD plus radiotherapy demonstrated no significant progression-free survival difference between the treatment arms, but this trial accrued relatively small numbers of patients.154 A phase III North American study assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin lymphoma to treatment with ABVD alone for four to six cycles or subtotal nodal radiation therapy, with or without ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. After a median followup of 11.3 years, the overall survival (OS) was 94 percent among those receiving ABVD alone, compared to 87 percent for those receiving subtotal nodal radiation therapy (p = 0.04). The rates of freedom from disease progression were 87 percent and 92 percent in the two groups, respectively (p = 0.05). The investigators concluded that treatment with ABVD therapy alone was superior because of a lower rate of death from secondary malignancies and other causes,155 although critics have emphasized that the large fields and high doses of radiotherapy used in this trial are obsolete and that modern radiotherapy techniques would be anticipated to have much more favorable outcomes. In a European trial, the epirubicin, bleomycin, vinblastine, prednisone (EBVP) regimen was tested against the same chemotherapy plus 20- or 30-Gy involved-field radiotherapy.156 Inferiority of the EBVP combination without radiotherapy resulted in the trial's early closure. A Cochrane meta-analysis of randomized controlled trials comparing chemotherapy alone with combined modality therapy concluded that adding radiotherapy to chemotherapy improves tumor control and OS in patients with early stage Hodgkin lymphoma.157
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Current studies are focused on assessing the potential role of interim FDG-PET scanning as a means of identifying patients (PET-negative) for whom radiotherapy can be omitted. The European Organization for Research and Treatment of Cancer (EORTC), the Lymphoma Study Association (LySA), and Fondazione Italiana Linfomi (FIL) H10 trial randomized 1137 patients with untreated supradiaphragmatic clinical stage I/II cHL to either standard therapy or an experimental, PET-response-adapted approach. Patients on the trial were stratified into favorable and unfavorable cohorts based on the presence or absence of adverse risk factors (age ≥50 years, more than four involved nodal areas, presence of mediastinal bulk [mediastinum-to-thorax ratio ≥0.35], or ESR ≥50 mm without B symptoms or ESR ≥30 mm with B symptoms).101 The favorable group was randomized to either standard therapy with three cycles of ABVD chemotherapy followed by involved nodal radiotherapy (30 Gy + 6 Gy boost), or “experimental therapy” in which patients whose interim PET scans after two cycles of ABVD were negative received two more cycles of ABVD (total of four cycles) but no radiotherapy. Patients in the experimental arm who had FDG-avid foci of disease after two cycles of ABVD were switched to the BEACOPP-escalated regimen for 2 cycles followed by involved nodal radiotherapy. An independent data monitoring committee stopped the study after a median followup of 1.1 years because of inferior results in the experimental group, with a 1-year progression-free survival of only 94 percent compared to 100 percent in patients treated on the standard arm (p = 0.017). The independent data monitoring committee mandated that all patients on the experimental arm be crossed over to receive involved nodal radiotherapy.101 Interestingly, the opposite conclusion was reached by investigators in England conducting a similarly designed trial, dubbed the “RAPID” trial.102 In this study, patients with early stage cHL were given three cycles of ABVD followed by a PET scan. Patients who were PET-negative after three cycles of ABVD were randomized to either receive 30 Gy of involved field radiotherapy or no further treatment. Patients who were PET-positive after three cycles received a fourth cycle of ABVD followed by involved field radiotherapy. An intent-to-treat analysis of the randomized PET-negative population revealed a 3-year progression-free survival of 94.5 percent in the combined modality group compared to 90.8 percent in those receiving only three cycles of ABVD (p = 0.23). An analysis of the data according to the treatment actually received revealed a 3-year progression-free survival of 97 percent in the combined modality group compared to 90.7 percent in the ABVD-alone group (p = 0.03). There were no statistically significant differences in OS between the groups (97.1 vs. 99.5 percent, respectively; p = 0.07). The investigators conducting this trial concluded that the inferior progression-free survival in the group receiving ABVD alone was acceptable in order to avoid late complications associated with radiotherapy. In view of the conflicting conclusions derived from these two large phase III trials, the role of interim FDG-PET/CT imaging in early stage cHL remains controversial. Nevertheless, the National Comprehensive Cancer Network has incorporated interim PET-imaging into their guidelines, suggesting that early stage cHL patients who are PET-negative after two cycles of ABVD may be treated with chemotherapy alone, without radiotherapy.158
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The advisability of administering bleomycin to patients over the age of 60 with classical Hodgkin Lymphoma (cHL) has been questioned due to the high risk of severe bleomycin-associated pulmonary toxicity in this age group. The German Hodgkin Disease Study Group has explored the feasibility, toxicity, and efficacy of combination chemotherapy with either ABVD or AVD in 287 early-stage favorable HL patients over the age of 60 in German Hodgkin Study Group studies HD10 and HD13.159 Patients in these studies were randomized to therapy with either 2 cycles of ABVD (n = 137) or 2 cycles of AVD (n = 82), followed by involved-field radiotherapy (IFRT), or to 4 cycles of ABVD+IFRT (n = 68). Grade III–IV adverse event rates were similar in patients receiving 2 cycles of AVD and 2 cycles of ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4 cycles of ABVD (65%). Bleomycin lung toxicity was rare in patients receiving 2 cycles of either ABVD or AVD but occurred in 7 of 69 patients (10%) randomized to 4 cycles of ABVD, with 3 fatal toxicities. From these findings, it was concluded that 2 cycles of bleomycin can be given safely to elderly patients with HL but that bleomycin should be omitted from subsequent cycles, in patients planned to receive more than 2 cycles of chemotherapy, due to the high risk of severe toxicity of bleomycin in this situation.
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UNFAVORABLE LIMITED-STAGE HODGKIN LYMPHOMA
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Patients with “unfavorable” prognostic factors (large tumor bulk defined as a mass 10 cm or larger in diameter or more than one-third of the transthoracic diameter, an ESR of 50 or greater, three or more sites of tumor involvement, the presence of B symptoms, or the presence of extranodal sites [see Table 97–4]) require more intensive treatment than do patients not exhibiting any of these features.158 The EORTC and the Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported results from a randomized study (H9U) in which such “unfavorable” early stage patients were randomized to treatment with either four or six cycles of ABVD or six cycles of BEACOPP, each followed by 30-Gy involved-field radiotherapy.156 No significant differences were observed among these three treatment arms, establishing four cycles of ABVD and 30 Gy of involved field radiotherapy as a standard of care for these patients. The GHSG subsequently randomized 1395 patients with unfavorable early stage Hodgkin lymphoma to four cycles of either ABVD or BEACOPPbaseline followed by either 20 Gy or 30 Gy of involved field radiotherapy. In this study, four cycles of ABVD followed by 30 Gy of radiotherapy was the best approach, affording an 85 percent rate of “freedom from treatment failure” and an OS rate of approximately 95 percent after 5 years, while maintaining a favorable toxicity profile.160 The administration of only 20 Gy of radiotherapy following ABVD was found to be clearly inferior to the other three treatment arms which all administered 30 Gy to this unfavorable group of patients. The subsequent GHSG HD14 study reported an advantage in progression-free survival for two cycles of escalated BEACOPP and two cycles of ABVD plus radiation therapy compared to four cycles of ABVD–radiation therapy, in a specified interim analysis, though no OS benefit was seen.161 After 3 years, 90 percent of ABVD–radiation therapy patients were disease-free compared to 96 percent treated with the BEACOPP–ABVD–radiation therapy regimen. The EORTC//LySA/FIL H10 trial randomized both favorable and unfavorable early stage patients to either standard therapy or experimental, PET-response adapted therapy.101 Of the 519 “unfavorable” patients evaluated in the interim analysis, 251 were randomized to standard ABVD for four cycles followed by 30 Gy of involved nodal radiotherapy, and 268 were randomized to PET-response adapted therapy. Patients on the experimental arm received six cycles of ABVD without any radiotherapy if the PET scan was negative after the second cycle of ABVD, whereas PET-positive patients were switched to BEACOPPescalated for 2 cycles followed by radiotherapy. An independent data safety monitoring board stopped this trial after a median followup of only 1.1 years because of worse outcomes on the experimental, PET-response adapted arm, with 16 relapses in 268 cases compared to only nine relapses of 251 cases on the standard arm (hazard ratio of 2.4; 95 percent confidence intervals 1.4 to 4.4).101
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ABVD became the standard therapy for advanced Hodgkin lymphoma by proving to be superior to the MOPP chemotherapy and equal to, but less toxic than, hybrid or alternating combinations with MOPP.141,142,162,163-165 Specifically, the incidence of secondary myelodysplasia, leukemia, and sterility was less with ABVD. The GHSG developed the BEACOPP regimen (see Table 97–3) based upon mathematical modeling that indicated a moderate increase in chemotherapy dose intensity would result in a significant increase in the cure rate. In the original HD9 study, BEACOPP was given in “standard” and “escalated” versions, the latter facilitated by granulocyte colony-stimulating factor use, and was compared with the cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone (COPP)–ABVD regimen.143 Patients with initial tumors equal to or greater than 5 cm or residual radiographic disease received 36-Gy radiotherapy after chemotherapy. The 5- and 10-year results demonstrated a significant progression-free and OS advantage for escalated BEACOPP compared to COPP–ABVD.143,144 The cure rates in excess of 80 percent for escalated BEACOPP are the best ever recorded for a large phase III trial in advanced Hodgkin lymphoma. The superiority of escalated BEACOPP was observed regardless of the clinical international prognostic score.124 Despite these outcomes, BEACOPP has not been universally accepted as the new standard in advanced Hodgkin lymphoma because of concerns about the acute toxicity, which includes greater need for hospitalization and transfusion, and late toxicity, which includes male and female sterility and an increased risk of secondary leukemia.166-169 In addition, approximately two-thirds of patients received radiotherapy in the HD9 study. Two randomized clinical trials from Italy subsequently confirmed the superiority of BEACOPP over ABVD for the end point of progression-free survival.170,171 In the first trial, BEACOPP (four escalated dose cycles plus two standard cycles) was compared to ABVD; all patients were to receive consolidation radiotherapy for bulky or residual disease. BEACOPP yielded significantly superior progression-free survival compared to ABVD although no difference in OS was observed.170 In the second study, patients were randomized to ABVD versus four cycles of standard and four cycles of escalated BEACOPP with preplanned retreatment and high-dose therapy and autologous transplantation for treatment failures.171 This study also showed a significantly higher progression-free survival for the BEACOPP arm but no difference in OS (Table 97–5). The EORTC 20012 Trial randomized patients with “high-risk” advanced stage Hodgkin lymphoma with an international prognostic scale score of 3 to 7124 to treatment with either BEACOPP (four escalated cycles + four standard cycles) or ABVD.172 Progression-free survival was improved in the BEACOPP arm but there was no statistically significant improvement in event-free or OS compared to ABVD.172 In each of the four cited trials, the hazard ratio for relapse with BEACOPP was approximately 0.5. Standards of care in advanced Hodgkin lymphoma continue to be debated in view of the lack of a survival benefit with the BEACOPP program, which benefits approximately 15 percent of patients while exposing 100 percent of patients to more toxicity.
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Efforts to reduce the risk of treatment-related morbidity of escalated BEACOPP have included studying the combination of four cycles of escalated and four cycles of standard BEACOPP and eliminating radiation therapy. In the GHSG HD12 trial, four standard cycles of BEACOPP plus four escalated cycles performed similarly to eight cycles of escalated BEACOPP, with freedom from treatment failure rates of 85 percent and 86 percent, respectively, 5 years after treatment. In this study, there was a slight trend for worse failure-free survival in patients with residual radiographic masses on end-of-treatment CT imaging who did not received consolidative radiotherapy (90 percent after 5 years with radiotherapy and 87 percent without it, p = 0.08).175 The subsequent HD15 trial randomized 2182 patients with newly diagnosed advanced stage cHL to receive either eight cycles of BEACOPPescalated, six cycles of BEACOPPescalated, or eight cycles of the BEACOPP-14 regimen. Patients with a persistent mass after chemotherapy measuring 2.5 cm or larger that was FDG-avid on an end-of-treatment FDG-PET imaging received consolidative radiotherapy (30 Gy). Freedom from treatment failure was similar for all three treatment arms but 5-year OS was significantly better for patients receiving six cycles of BEACOPPescalated than for 8 cycles of BEACOPPescalated (91.9 percent vs. 95.3 percent) as a result of higher treatment-related mortality and secondary malignancies with the latter regimen.176
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Numerous investigations are underway to determine if interim PET scans can direct more-intensive treatment with escalated BEACOPP to the subgroup that benefits.95,97,100,177,178 Likewise, interim and end-of-treatment PET scans are being used to direct the use of consolidative radiotherapy.95,177-180 Although there is great enthusiasm regarding this approach to direct subsequent treatment, it is notable that the majority of patients remaining PET-positive after four cycles of escalated BEACOPP appear to be cured by the planned therapy, in contrast to findings with ABVD.180
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The Stanford group took an alternate approach to advanced Hodgkin lymphoma by abbreviating the duration of therapy and reducing cumulative drug doses in the Stanford V regimen.181 This approach appeared highly successful in institutional and phase II cooperative group trials; however, three randomized controlled trials have failed to show improved progression-free survival compared to standard ABVD chemotherapy.182,183,174 The impressive efficacy of brentuximab vedotin in relapsed and refractory cHL184,185 has also led to investigations into its incorporation into front-line regimens. This drug consists of an anti-CD30 monoclonal antibody conjugated to a highly potent antitubulin cytotoxic drug, monomethyl auristatin E. Phase I studies revealed unacceptable pulmonary toxicity when brentuximab vedotin was incorporated into the full ABVD regimen,186 presumably as a result of augmenting the pulmonary toxicity of bleomycin. Omission of bleomycin, however, allows safe and effective combination therapy with brentuximab vedotin concurrently with AVD, with 96 percent of patients achieving complete remission.186 An international phase III randomized comparison of standard ABVD versus brentuximab vedotin + AVD is underway for patients with advanced cHL.
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The use of radiotherapy as a consolidation to combination chemotherapy in advanced cHL is controversial. Encouraging data from single institutions in adults and children were not borne out in randomized trials, some of which were criticized as underpowered. Furthermore, chemotherapy regimens have evolved over the time span of these studies. The application of 30 Gy involved-field radiotherapy to patients in complete remission after MOPP–ABV was studied in an adequately powered phase III trial.187 No significant difference in failure-free survival was observed. Of note, all patients in partial remission received 40 Gy on this study and their outcome was not different from complete remission patients. The GHSG HD12 study randomized patients to observation or consolidation radiotherapy, with the incorporation of a central review panel, following BEACOPP. The final analysis of this study reported a slight decrease in the freedom from treatment failure if radiotherapy was omitted in patients who had persistent radiographic abnormalities on CT imaging after chemotherapy (90.4 percent vs. 87 percent after 5 years), but no difference was seen in patients with bulk disease in complete response after chemotherapy. Unfortunately, FDG-PET imaging was not routinely used in this trial.175 The two Italian studies comparing ABVD with BEACOPP mentioned above routinely incorporated consolidation radiation therapy for residual or bulky disease.170,188 The HD15 study limited the use of radiotherapy to patients with positive PET scans after four cycles of chemotherapy. With this approach, only 12 percent of patients received radiotherapy and the progression-free survival rate among PET-negative patients, who did not receive radiotherapy, was 96 percent after 1 year.176 In sum, the data do not support the routine use of radiotherapy following a full course of chemotherapy in advanced Hodgkin lymphoma. However, the role of this potent treatment in patients with an early incomplete response or following a brief course of chemotherapy is likely to be more significant.180,181
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NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA
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NLPHL presents as asymptomatic, limited-stage disease in most (~80 percent) patients.103,104,109 Peripheral lymph nodes in the neck, axilla, or groin are commonly involved as stage IA disease. The European Task Force on lymphoma reported a 96 percent complete response rate and 99 percent and 94 percent 8-year disease-specific survival for stages I and II disease, respectively.109 Because of the low likelihood of occult disease in nodular lymphocyte-predominant Hodgkin lymphoma and the tendency for the disease to remain localized for years, regional radiation therapy is considered the treatment of choice for early stage disease.104 Analyses from the GHSG demonstrate that outcomes with limited radiation therapy are comparable to the use of more extensive radiation and combined modality regimens.189 For the 20 percent of patients who present with stage III or IV disease, most authorities advise treatment with ABVD-based chemotherapy following the paradigms developed for cHL,104 although some contend that alkylator-based regimens such as rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), prednisone (R-CHOP) may be equally effective and less toxic.190 Because of the consistent high level expression of the CD20 antigen on the surface of NLPHL cells, the monoclonal antibody rituximab has been tested in this entity. Initial studies were conducted using single-agent rituximab in relapsed and refractory cases and demonstrated response rates of 94 to 100 percent with median durations of remission of 33 to 60 months, with longer remissions observed when maintenance rituximab was used.191,192 Based on these findings,, and the low toxicity of rituximab, some authorities have extrapolated its use to the frontline setting,190 adding it to radiotherapy for stage I or II patients and to ABVD for stage III or IV disease, although few data been published concerning the frontline use of this agent in NLPHL.
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Historically, patients with cHL who relapsed after a full course of chemotherapy had a low chance for cure with second-line treatment, with the duration of initial remission a significant predictor of subsequent response and relapse-free survival. High-dose therapy and autologous blood stem cell transplantation improved the outlook for such patients and is routinely employed in first relapse for most patients younger than age 65 years, based on institutional and phase III trial experience.193,194 Cure rates with transplantation range from 40 to 60 percent with transplant-related mortality less than 5 percent.195,196 High-dose regimens include BEAM (carmustine, etoposide, cytarabine, melphalan), CBV (cyclophosphamide, carmustine, etoposide), and total-body irradiation with cyclophosphamide and etoposide. Consolidation radiotherapy is often employed to sites of pretransplantation bulk disease. The superiority of any single transplant conditioning regimen has not been definitively established; however, the use of high-dose sequential therapy coupled with tandem autologous transplantation is being tested in randomized trials.197,198 In most cases, second-line chemotherapy with ICE (ifosfamide, carboplatin, etoposide), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), DHAP (dexamethasone, cytarabine, cisplatin), or brentuximab vedotin is used to achieve a minimal disease state prior to stem cell mobilization and transplantation.199-201 Treatment failures following autologous transplantation present a challenge, with longevity directly related to the time to relapse after transplantation. Allogeneic transplantation in multiply recurrent Hodgkin lymphoma has been limited by significant transplant-related mortality, although long-term disease control has been observed in a small subset together with anecdotal evidence of a graft-versus-Hodgkin antitumor effect. Nonmyeloablative transplantation conditioning regimens reduce transplant-related mortality but disease recurrence continues to present a major challenge, with failure-free survivals in the 20 to 30 percent range.201-203
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As mentioned above, the anti-CD20 antibody rituximab achieves high response rates in relapsed NLPHL and can be used as retreatment or as an extended-treatment regimen.191,204 Monoclonal antibodies directed against the CD30 antigen are well tolerated in classical Hodgkin lymphoma but have limited therapeutic value.205 However, the anti-CD30 antibody–drug conjugate, brentuximab vedotin has major activity with 96 of 102 patients with relapsed or refractory cHL experiencing tumor shrinkage in a phase II clinical trial, including 75 percent with objective remissions and 34 percent with complete remissions.185 The agent has also shown major efficacy when used as a bridge to allogeneic transplantation206 or in patients relapsing after allogeneic stem cell transplantation.207 The major toxicity of this agent when used as a single agent is peripheral neuropathy, though mild to moderate cytopenias also occur. Nivolumab and pembrolizumab are PD-1 blocking antibodies that have recently been shown to have remarkable efficacy in patients with relapsed or refractory cHL, with objective remission rates of up to 87 percent observed in trials enrolling heavily pretreated patients.208