Early-Stage Nonbulky Hodgkin Lymphoma

The transition from extended-field radiation therapy (EFRT) to combined-modality therapy with chemotherapy and involved-field radiation therapy (IFRT) in the 1990s represented a major step forward in the treatment of limited-stage HL.26,27 Because of concerns of serious late toxicities (described in detail later), there is universal agreement that the dose and field of radiation should be minimized in the treatment of early-stage HL. DeBruin and associates demonstrated a significant reduction in the incidence of second breast cancers in women treated with mediastinal RT compared with mantle RT for HL, and a meta-analysis of HL trials by Franklin and associates showed a marked decrease in second cancers in patients receiving IFRT compared with EFRT.^28,29 However, because mediastinal nodes are involved in the majority of patients with HL, most patients undergoing RT for HL will continue to have at least modest exposure to the heart, lungs, and breasts regardless of efforts to administer only involved-field or even involved-nodal RT. Unfortunately, efforts to completely eliminate radiation for the majority of patients with early-stage HL continue to meet with significant resistance. The 2012 publication of a randomized trial of an ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine) alone versus radiation-based therapy in limited-stage HL showing for the first time a survival advantage in the chemotherapy-alone arm, despite an inferior progression-free survival (PFS), has rekindled the debate.²⁵ Current guidelines and recommendations continue to support either chemotherapy alone or combined-modality therapy in the treatment of nonbulky early-stage HL.³⁰

The specifics of combined-modality therapy for early-stage HL are generally based on the results of two randomized trials from the German Hodgkin Study Group, HD10 and HD11. For patients with the most favorable presentation, two cycles of ABVD and 20 Gy of IFRT resulted in a 5-year freedom from treatment failure (FFTF) of 91% and overall survival rate (OS) of 97%.³¹ There was no advantage to four cycles of ABVD or 30 Gy of RT in this subset of patients. Importantly, and often misunderstood in the general oncology community, patients eligible for this study (HD10) included only those with disease limited to no more than two sites, no extranodal or bulky disease, and ESR less than 50 if no B symptoms and less than 30 in the presence of B symptoms. Patients with early-stage disease not meeting the eligibility criteria for HD10 were treated on the HD11 trial comparing four cycles of ABVD to four cycles of standard-dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) followed by 20 or 30 Gy IFRT.³² The two chemotherapy regimens yielded equivalent results with less toxicity in the ABVD arm, and the outcomes were superior for those receiving 30 Gy compared with 20 Gy, resulting in the recommendation of four cycles of ABVD plus 30 Gy RT in this less favorable subset. At 5 years, FFTF was 85% and OS was 95%.

Advocates of chemotherapy alone for nonbulky early-stage disease acknowledge the increased failure rate of 5% to 8% when RT is eliminated.25,33 However, with a follow-up duration of 4 to 5 years, no trial comparing chemotherapy alone to combined-modality therapy in early-stage disease has shown a survival advantage for combined modality therapy, likely because second-line strategies, often including RT, result in durable disease control in nearly half of patients with relapsed disease. As alluded to earlier, the National Cancer Institute of Canada (NCIC) study (HD.6) comparing ABVD alone with subtotal nodal irradiation (STNI), with or without ABVD, in 405 patients with nonbulky stage I to IIA HL showed a 12-year PFS of 87% versus 92% (P = .05) in favor of the RT arm of the study but remarkably a 12-year OS of 94% for ABVD alone compared with 87% for those receiving STNI (P = .04). Importantly, 12-year follow-up does not yet reflect the dramatic increase in cardiovascular disease and second malignancies starting 15 to 20 years after primary therapy with RT (Fig. 105-3).³⁴ Critics condemn this study, owing to the use of EFRT in the control arm, arguing that the OS of the RT arm does not reflect modern RT techniques and fields. Regardless of this criticism, the 12-year event-free survival (EFS) of 87% in the ABVD-alone arm of the study compares favorably with the 5- to 8-year EFS rates of 86% to 87% reported in the HD10 and HD11 trials, respectively, of ABVD in combination with limited dose and field RT. In an effort to more accurately compare the results of these trials because of differences in eligibility, staging, end points, and follow-up duration, investigators performed an individual patient-data comparison of HD10 and HD11 and the ABVD-alone arm of HD.6.³⁵ Patients were included if eligible for one of the combined-modality studies as well as the HD.6 study. In 406 patients, the authors concluded that time to progression (hazard ratio [HR], 0.44, 95% confidence interval [CI], 0.24 to 0.78) and PFS (HR, 0.71; CI, 0.42 to 1.18) but not OS trended to being superior in patients treated with combined-modality therapy (HD10/HD11) versus ABVD alone (HD.6). There were no differences in outcomes for patients achieving a complete response (CR) by CT after two cycles of ABVD. IFRT appeared most beneficial to patients who did not achieve an early CR, which provides support for the role of interim response assessment.

The optimum number of cycles of chemotherapy is not defined for patients receiving chemotherapy alone. In the NCIC HD.6 study, 69/196 (35%) of patients treated with ABVD alone achieved CR by CT criteria after two cycles of ABVD.²⁵ Of these 69 CR patients, 57 received a total of four cycles of ABVD (per protocol) and 12 received six cycles (physician decision) with a 5-year freedom from disease progression of 95%, compared with 81% for the 113 patients not in radiographic CR after two cycles (Fig. 105-4). In the small subset of patients with a CR by CT after two cycles of ABVD, a total of four cycles appears adequate. The German Hodgkin Study Group recently adopted the “2 + 2 regimen” for patients with early unfavorable HL based on the results of the HD14 trial.³⁶ Patients were randomized to four cycles of ABVD (ABVD arm) or two cycles of escalated (esc) BEACOPP followed by two cycles of ABVD (2 + 2 arm). Patients in both arms of the study received 30 Gy IFRT after chemotherapy. The 5-year FFTF was superior in the 2 + 2 arm (94.8%) compared with the ABVD arm (87.7%) (P < .001), but there was no difference in OS between the two arms. Grade 3 and 4 toxicities were significantly more frequent in the 2 + 2 arm compared with the ABVD arm. In univariate and multivariate analyses, only large mediastinal mass and elevated ESR were predictors for PFS events.

Based on compelling data from Gallamini and Hutchings showing a 2-year PFS of 12% for HL patients with a positive PET scan after two cycles of ABVD compared with 95% for patients with a negative interim PET, the use of interim PET has become widespread in standard practice and is the focus of most current clinical trials in both early and advanced HL.³⁷ Current studies are examining the use of early metabolic CR by PET/CT to determine the number of cycles of chemotherapy, the intensity of the chemotherapy regimen, and which patients should receive RT.

It is unclear whether the dramatic predictive value of a positive interim PET applies to patients with early-stage HL. In a small study of 57 patients with stage I or II HL, those patients with a positive PET after two cycles of ABVD still had an approximately 75% chance of durable remission with additional ABVD chemotherapy and consolidative IFRT.38,39 Investigators at the Dana Farber Cancer Institute also reported outcomes for 73 patients with HL, 86% with limited stage, referred for consolidative RT, including 20 of 43 patients with a positive interim PET scan and 13 of 73 patients with a positive PET scan at completion of chemotherapy. After IFRT, the 2-year failure-free survival (FFS) was 85% for patients with a positive interim PET and 69% versus 95% for patients with a positive versus negative PET, respectively, at the completion of all chemotherapy.⁴⁰

Whether a PET-directed approach will allow us to safely minimize chemotherapy cycles and avoid RT is the subject of several ongoing large randomized trials. As these trials complete accrual and results mature, we hope to have a definitive answer as to whether three to four cycles of ABVD alone will be sufficient therapy for the majority of patients with early-stage HL and whether ABVD + RT or alternatively escBEACOPP + RT will be sufficient therapy for patients with less than a complete metabolic response after two cycles of ABVD. Preliminary results of the first completed randomized trial evaluating interim PET-directed therapy in early-stage HL, the UK RAPID trial, provide the earliest support for this concept.⁴¹ Eligibility for the RAPID trial included nonbulky HL without regard to other risk factors. All patients received three cycles of ABVD and were restaged with PET/CT. Patients with a negative PET, as defined by a score of 1 or 2 on the London Deauville visual analog scale, were then randomized to receive IFRT versus observation.⁴² Patients with a positive interim PET went on to receive one additional cycle of ABVD followed by IFRT. In this study, 74.6% of patients had a negative PET scan after three cycles of ABVD. With a median follow-up of 45.7 months, 91.4% of interim PET-negative patients (384/420) and 86.9% of interim PET-positive patients (126/145) are alive and progression free. The 3-year PFS and OS rates were 93.8% and 97%, respectively, in the 209 PET-negative patients randomized to IFRT and 90.7% and 99.5%, respectively, in the 211 PET-negative patients randomized to no further treatment. The PFS survival risk difference of −2.9% [95% CI, −10.5, 1.4%] marginally exceeded the acceptable noninferiority margin of −7%. These very encouraging results support the use of chemotherapy alone in the 75% of patients with early negative interim PET/CT.

Early-Stage Bulky Hodgkin Lymphoma

Despite a paucity of data, the standard treatment for patients with early-stage bulky HL is combined-modality therapy.27,34 The early-stage bulky presentation of HL is common in young women, the population most at risk for late effects of RT, primarily breast cancer. No randomized trials in early-stage bulky HL have specifically addressed the role of RT. The recent intergroup trial E2496 enrolled 854 patients, including 268 with stage I/II bulky disease.⁴³ The patients were treated with ABVD plus modified IFRT to 36 Gy for patients with bulky mediastinal disease or with the Stanford V regimen plus modified IFRT to 36 Gy for sites larger than 5 cm in maximum transverse dimension or in the presence of macroscopic splenic disease. In the patients with bulky disease, the 5-year FFS and OS were 82% and 94%, respectively, with no difference between the study arms. This subgroup analysis provides the “standard” against which trials investigating a reduction or elimination of RT should be compared to determine if the benefits of RT in early-stage bulky disease outweigh the significant risks. The use of fluorodeoxyglucose (FDG)-labeled PET at the end of treatment to guide consolidative radiation was investigated in patients with residual abnormalities on CT.⁴⁴ Despite omission of RT in patients with a negative end of treatment PET scan, there was no difference in the 3-year time to progression between the patients with bulky disease and those without bulky disease (86% vs. 91%, P = .71). An Italian study of RT versus observation in 160 patients with “bulky” (≥5 cm) disease and a negative end of treatment PET revealed that 14% of patients who did not receive radiation experienced relapse at a median follow-up of 40 months compared with 4% of patients who received RT.⁴⁵ Until randomized trials are completed, the standard of care for bulky HL remains combined-modality therapy in most centers.

Advanced-Stage Hodgkin Lymphoma

The majority of patients with stage III/IV HL receive six cycles of ABVD chemotherapy, the standard treatment for more than 2 decades. The Hasenclever International Prognostic Score (IPS) is used to predict prognosis of patients with advanced-stage HL treated with ABVD (see Table 105-2).⁴⁶ In the original publication, the 5-year FFP rates were 70% for those with none to three risk factors compared with 47% for those with four or more high-risk features. A more recent publication examining the outcomes of patients with advanced-stage HL treated in British Columbia between 1980 and 2010 according to the IPS (Table 105-3) showed more favorable 5-year PFS rates of 81% for patients at lower risk (IPS 0 to 3) and 65% for those at high risk (IPS 4 to 7).⁴⁷ Several reasons are hypothesized for superior PFS rates, including improved diagnostic accuracy resulting in elimination of patients with non-Hodgkin lymphoma, better dose-intensity preservation with current recommendations to treat with full-dose ABVD every 2 weeks regardless of day of treatment neutrophil count, more precise staging with PET/CT resulting in upstaging of perhaps more favorable advanced-stage disease, and anthracycline-based therapy in all patients compared with only 80% of patients in the original series.^49–49 The routine use of autologous stem cell transplant (ASCT) in relapsed HL likely accounts for the improvement in OS. Although the IPS continues to delineate outcomes in HL, the narrower range of outcomes makes it more difficult to justify changes in clinical management based on the initial IPS.

The German Hodgkin Study Group continues to advocate the use of escBEACOPP as initial therapy in all patients with advanced stage HL. Initially reported in 2003, a large randomized trial comparing eight cycles of escBEACOPP to COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABVD showed that escBEACOPP resulted in better tumor control and OS.⁵⁰ Ten-year follow-up of the trial showed FFTF and OS rates of 64% and 75% for COPP/ABVD compared with 82% and 86% for escBEACOPP (P < .0001).⁵¹ There was no significant difference in FFTF or OS for patients 60 to 65 years, and escBEACOPP is not recommended in patients 60 years of age or older secondary to unacceptable acute toxicities. Despite the improved FFTF, and perhaps even a survival advantage, physicians outside Germany hesitate to recommend escBEACOPP because of toxicity concerns. Acute hematologic toxicity is high with escBEACOPP, with grade 3 to 4 infections occurring in 22% of patients. Acute myeloid leukemia (AML) developed in 3% of patients on the escBEACOPP arm of the trial. EscBEACOPP results in azoospermia and infertility in the majority of male patients and induces premature menopause in 40% of women younger than age 30 years and 70% of women 30 years of age or older.^54–54 An analysis of female survivors treated on the German Hodgkin Study Group HD14 trial revealed a reduced ovarian reserve (as determined by hormone levels) in patients treated with two cycles of escBEACOPP + two cycles of ABVD compared with four cycles of ABVD.⁵⁵ However, the authors reported that this “2 + 2 regimen” in combination with gonadotropin-releasing hormone (GnRH) analogs did not compromise fertility, because motherhood rates were equivalent to the German normal population. Conflicting reports regarding the use of oral contraceptives and GnRH analogs to protect the ovarian follicle pool have been published.⁵⁶ A randomized trial of six versus eight cycles of escBEACOPP in advanced-stage HL showed a more favorable toxicity profile and improved 5-year OS with six cycles.⁵⁷ Secondary AML/MDS (myelodysplastic syndrome) occurred in 0.3% of those receiving six cycles compared with 2.7% for eight cycles, and acute treatment-related deaths were 0.8% with six cycles versus 2.1% for eight cycles.

In three other randomized trials of escBEACOPP versus ABVD, escBEACOPP was not associated with a survival advantage, despite a lower rate of relapse,58,59 All three trials, in an effort to reduce both acute and long-term toxicity, administered a slightly less intensive BEACOPP regimen than the German Hodgkin Study Group with four cycles of escBEACOPP and two cycles of standard BEACOPP in two trials and four cycles of escBEACOPP and four cycles of standard BEACOPP in one study. The lack of a survival difference in these trials is likely due to the better prognosis after second-line therapy for patients initially treated with ABVD compared with escBEACOPP. In one study, 33% (15/45) of the patients who failed ABVD remained in continuous CR after salvage therapy, compared with only 15% (3/20) of the BEACOPP failures at a median follow-up time of 61 months.⁶⁰ Failure of many physicians to embrace the escBEACOPP regimen is a result of physicians choosing to expose fewer numbers of patients to sterilizing and potentially leukemogenic therapy. The tradeoff of this choice is that a higher percentage of patients will need salvage therapy, including ASCT. ASCT is now associated with less than 2% acute mortality in most centers and in many ways may be a more tolerable treatment than six cycles of escBEACOPP.

An 854-patient U.S. intergroup study compared ABVD with Stanford V chemotherapy in advanced-stage HL and demonstrated no advantage to the Stanford V regimen.⁴³ Five-year FFS was 74% for ABVD compared with 71% for the Stanford V regimen (P = .32). The 5-year OS was 88% in both patient groups. The abbreviated Stanford V regimen was inferior to ABVD in patients with an IPS of 3 to 7 (5-year PFS 57% vs. 67%, P = .02) and was associated with more hematologic toxicity and peripheral neuropathy.

As discussed in treatment of early-stage disease, the interim PET/CT scan may allow therapy to be tailored more accurately than the initial IPS. In the joint report from an Italian-Danish study evaluating the prognostic significance of early interim PET scans after two cycles of ABVD (PET-2), only PET-2 was significant in a multivariate analysis that included all IPS factors.³⁷ Still under investigation is whether altering therapy on the basis of the interim PET will result in more favorable outcomes. Dann and colleagues described 77 patients treated with two cycles of standard-dose BEACOPP followed by a gallium-67 or PET/CT scan.⁶¹ Twelve patients had a positive interim gallium-67 or PET/CT scan, and therapy was intensified to escBEACOPP, with only two relapses occurring after intensification of the treatment. In a retrospective review of 154 patients with newly diagnosed advanced-stage HL treated in 2006 and 2007 at one of nine Italian or U.S. centers with two cycles of ABVD followed by escBEACOPP × 4 plus standard BEACOPP × 4 if an interim PET/CT scan was positive, and an additional four cycles of ABVD if PET/CT was negative, the 2-year FFS was 62% for PET-positive patients and 95% for PET-negative patients (P < .0001).⁶² These results are in stark contrast to the 2-year PFS of 12% reported by Gallamini and colleagues for patients with a positive interim PET/CT who continue treatment with ABVD.³⁷ With approximately 20% of patients expected to have positive interim PET scans, the outcomes in this subset of patients treated with more intensive therapy will be primarily observational. A randomized trial of standard chemotherapy versus intensified therapy for PET-positive patients in advanced HL will not be done, because of ethical concerns based on historical reports. In contrast to the U.S. and U.K. trials in which all patients are treated initially with ABVD and those with a positive interim PET are escalated to more intensive therapy, the German Hodgkin Study Group (HD18, NCT00515554) and Group d’Études des Lymphomes de l’Adulte (NCT01358747) are both conducting clinical trials in advanced-stage HL in which all patients initiate treatment with escBEACOPP and those with a negative interim PET are de-escalated to ABVD (Group d’Études des Lymphomes de l’Adulte) or two additional cycles of escBEACOPP (vs. six additional cycles) (German Hodgkin Study Group). The hope and expectation is that in the coming years physicians will be able to tailor therapy much more effectively by escalating to more toxic therapy only in the small subset of patients with an early positive interim PET and perhaps eliminating cycles or agents such as bleomycin in patients with a negative PET.

Prognosis at Relapse

Most prognostic models for relapsed HL include not only the disease and patient characteristics at relapse but also the response to initial salvage therapy. In practice, the response to the initial salvage regimen trumps all other prognostic features in the decision to proceed with ASCT. Currently, there are no clinical features at relapse that would prevent administration of standard salvage chemotherapy, with pretransplant response assessment, preferably by PET/CT, as the primary determinant of outcome. Older reports of ASCT results based on response to salvage therapy as determined by CT criteria show 5-year PFS rates of 60% to 69% for patients with a CR, approximately 40% for patients achieving a partial response (PR), and less than 20% for those with no response.88,89

Functional imaging, initially with gallium-60 and more recently FDG-PET, may improve pre-ASCT prognostication, especially in the subset of patients with a PR or stable disease by CT criteria. Table 105-4 summarizes the results of several small series showing ASCT outcomes based on pretransplant PET results. Nearly 80% of patients with a negative PET before a transplant remain in remission 3 to 5 years after ASCT. Because 23% to 41% of patients with a positive pre-ASCT PET will still experience a prolonged remission, most centers proceed to ASCT in this subset of patients, as long as there is no evidence of frank progression. Moskowitz and colleagues administered additional non–cross-resistant salvage therapy before ASCT in patients with a positive PET after first-line salvage.⁹⁰ Patients achieving a PET-determined CR after first-line salvage therapy and those with a PET-determined CR only after second-line salvage therapy had identical outcomes with an 80% 5-year EFS compared with less than 30% for those who remained positive (Fig. 105-5). Response to second salvage, a refined interpretation of “positive” PET results, or a model incorporating other high-risk clinical features specifically for the PET-positive group may allow better selection of the subgroup for whom alternatives to ASCT should be considered.

Clinical factors at relapse may complement prognostic information provided by the PET response to salvage therapy. Poor prognostic features consistently identified in multivariate analyses include time to relapse (≤12 mo. vs. >12 mo.), advanced clinical stage, anemia, B symptoms, and bulky and extranodal disease.93–93 The use of the IPS developed by Hasenclever for newly diagnosed advanced-stage HL has also been investigated in patients with relapsed HL.^89,94 Bierman and associates showed 10-year EFS rates were 38%, 23%, and 7% for patients with none to one (n = 27%), two to three (n = 53%) or four or more (n = 20%) of the seven IPS risk factors (P < .001).⁹⁴ Sirohi and colleagues reported a 5-year PFS rate of 60% for those with an IPS of 0 to 2 versus 32% for those with a score of 3 or more (P = .0001) immediately before ASCT.⁸⁹ In a model including B symptoms, extranodal disease, and initial response less than 1 year, 5-year EFS rates of 76% (none to one factor), 35% (two factors), and 8% (three factors) were reported.⁹⁵ Smith and colleagues stratified patients with relapsed HL into three groups based on risk factors of bulky and extranodal disease.⁹³ Patients with none, one, or two risk factors achieved a 6-year EFS of 65%, 47%, and 24%, respectively.

An international effort is needed to identify clinical or biological prognostic factors specifically in the patients who remain PET positive after first- or second-line salvage therapy.

Pretransplant Salvage Chemotherapy

The ideal pretransplant salvage regimen provides a high response rate, low toxicity, and minimal damage to stem cells, allowing the majority of patients to proceed without delay to ASCT. Overall and complete response rates for selected pretransplant salvage regimens are listed in Table 105-5. Most salvage regimens are designed to incorporate agents that are non–cross resistant to ABVD, such as ifosfamide, platinum, etoposide, gemcitabine, cytarabine, and corticosteroids. Unfortunately, no randomized trials have compared the effectiveness of conventional salvage regimens for relapsed HL. For those not achieving a PET-determined CR with first-line salvage, an alternate regimen should be considered before ASCT. For those receiving initial salvage with ICE, ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), or DHAP (cisplatin, cytarabine, dexamethasone), a gemcitabine-containing regimen such as GVD (gemcitabine, vinorelbine, liposomal doxorubicin) represents a reasonable second-line salvage option.^90,96 Alternatively, single-agent brentuximab vedotin (see later discussion under New Drugs) is approved as second-line salvage with reported response rates of 76% in relapsed HL with a 34% CR rate.^97,98 Brentuximab vedotin has been tested primarily in patients who have failed ASCT, which by definition is a more chemosensitive group than the group failing first-line salvage. Brentuximab vedotin as first-line salvage is under investigation in two single-center studies (NCT01393717, NCT01508312).

In retrospective analyses there appears to be no advantage to aggressive pretransplant regimens such as mini-BEAM (BCNU [carmustine], etoposide, cytarabine, melphalan), which are associated with higher morbidity, mortality, and stem cell toxicity.99,100 Based on retrospective data, Moskowitz and colleagues advocate intensifying salvage regimens for patients with high-risk features at relapse, specifically those with at least two of three poor prognostic features at relapse, including B symptoms, extranodal disease, and remission duration less than 1 year.⁹⁵ Patients with none to one risk factor received two cycles of standard ICE, those with two risk factors received one cycle of standard ICE and one cycle of augmented ICE (dose of ifosfamide and etoposide doubled), and those with three risk factors received one cycle of high-dose cyclophosphamide followed by one cycle of high-dose ICE requiring stem cell rescue. All responding patients went on to receive ASCT. Five-year EFS rates were approximately 50% for those with two risk factors and 40% for those with three risk factors compared with historical rates of 37% and 8%, respectively. Unfortunately, the complex approach advocated by some centers, with a 10-branch decision tree for a patient with relapsed HL, is difficult to implement across centers.⁹⁵

Role of Allogeneic Stem Cell Transplantation

Allogeneic SCT has the theoretical advantages of a tumor-free stem cell source, additional antitumor activity, and a decrease in secondary myelodysplastic syndrome (MDS) and acute leukemia. However, high treatment-related mortality with myeloablative allogeneic SCT has dampened enthusiasm for this approach. Reduced intensity conditioning (RIC-allo) or nonmyeloablative SCT decreases 1-year treatment-related mortality (7% to 25%) but is still associated with significant morbidity related to graft-versus-host disease and an increased risk for relapse (40% to 59%).¹⁰¹ Robinson and associates reported a 3-year PFS of 25% after RIC-allo in 285 patients with relapsed HL, 80% whom had undergone previous ASCT.¹⁰² Retrospective analyses suggest that RIC-allo may be superior to conventional salvage therapy in patients for whom ASCT failed, as shown in Figure 105-6.^103,104 Chen and colleagues showed very encouraging results of RIC-allo in patients treated with previous brentuximab vedotin.¹⁰⁵ Historically, HLA-matched related or matched unrelated donors have been the preferred donor source. Burroughs and associates reported a significantly higher 2-year PFS rate (51% vs. 23% to 29%), decreased relapse rate (40% vs. 56% to 63%), and significantly lower nonrelapse mortality for haploidentical donor transplants compared with HLA-matched transplants.¹⁰⁶ Responses after donor lymphocyte infusions provide evidence of graft versus HL effect.^109–109

New Drugs

The most promising new therapy for relapsed/refractory HL is brentuximab vedotin (SGN-35), an antibody-drug conjugate composed of an anti-CD30 antibody (cAC10) conjugated to monomethyl auristatin E (MMAE), a potent antimicrotubule agent.¹¹⁰ Brentuximab vedotin was approved by the U.S. Food and Drug Administration in 2011 for patients with relapsed or refractory HL after at least two prior lines of treatment. In a pivotal phase II trial, brentuximab vedotin had an overall response rate of 75% and CR rate of 34% in 102 patients with relapsed or refractory HL after ASCT, including 70% of patients with primary refractory HL.⁹⁷ Patients received a maximum of 16 cycles unless disease progression or prohibitive toxicity occurred. The median PFS was 5.6 months, and in patients who achieved a CR, the median duration of response was 20.5 months. Common brentuximab vedotin toxicities include peripheral sensory neuropathy (42%), neutropenia (19%), and diarrhea (18%). No febrile neutropenia or treatment-related deaths occurred in the phase II study. Peripheral sensory neuropathy is reversible in most patients. Three cases of progressive multifocal leukoencephalopathy have been reported in patients receiving brentuximab vedotin.¹¹¹ Brentuximab vedotin is contraindicated in combination with bleomycin given the increased incidence of severe and fatal pulmonary toxicity seen in a phase I study of brentuximab vedotin plus ABVD chemotherapy.¹¹²

Re-treatment with brentuximab in patients with relapsed HL who previously responded to brentuximab vedotin resulted in a 60% response rate in 15 patients, including three with complete remissions.¹¹³ Brentuximab vedotin may serve as a bridge to RIC-allo in responding patients who failed prior ASCT.¹⁰⁵ Additional studies are exploring the use of brentuximab as adjuvant therapy after ASCT, as well as in combination with AVD (ABVD without the bleomycin) as first-line therapy.

Other novel agents under investigation in relapsed/refractory HL include histone deacetylase (HDAC) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, immunomodulatory agents, and the bi-alkylator bendamustine. Panobinostat, a pan-HDAC inhibitor, showed modest activity in a phase II study in relapsed and refractory HL after ASCT.¹¹⁴ The overall response rate was 27% (4% CR) in 129 patients. The median duration of response was 6.9 months, and the median PFS was 6.1 months. The treatment was well tolerated, and the common grade 3 and 4 hematologic adverse events were manageable; only two patients (2%) experienced febrile neutropenia. A phase II trial of the mTOR inhibitor everolimus reported an overall response rate (ORR) of 47% (5% CR) in 19 patients with relapsed HL.¹¹⁵ The median duration of response was 7.1 months, and the median PFS was 6.2 months. Four patients (21%) experienced grade 3 or higher pulmonary toxicity, a known side effect of everolimus, and 2 patients developed infections considered at least possibly related to treatment. Lenalidomide, an immunomodulatory agent, showed modest activity in 38 patients with relapsed/refractory HL.¹¹⁶ The ORR was 18% (3% CR), the median duration of response was 6 months, and the median PFS was 4 months. The most common (≥15%) grade 3 or 4 adverse events were neutropenia and thrombocytopenia; grade 3 or 4 infections occurred in 3 patients (8%). A retrospective analysis of 41 patients treated with bendamustine reported a response rate of 58% (31% CR).¹¹⁷ The median duration of response was 9 months, and the median PFS exceeded 11 months. A prospective phase II study of bendamustine enrolled 36 patients with relapsed/refractory HL and reported an ORR of 57% (33% CR).¹¹⁸ The mean response duration was 5.7 months, but the PFS and OS rates have not been reported. Combinations of new agents with standard therapies are under investigation.

Second Cancers

Abandonment of the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen and alkylating agents in the primary therapy for HL has virtually eliminated the incidence of secondary acute leukemia related to primary therapy, except in those receiving escBEACOPP. Even with the alkylator-dense escBEACOPP regimen, reducing the number of cycles from eight to six has resulted in many fewer cases of acute leukemia.⁵⁷ Patients who experience relapse and undergo an ASCT continue to have a significant increased risk for leukemia.⁸⁹

Second solid tumors are significantly increased in patients treated with regional-field RT or EFRT and based on early follow-up of the HD10 and HD11 trials, likely represent a substantial risk even for those patients receiving a more limited RT field.31,32,34 Hodgson and associates evaluated second cancers among 18,862 HL survivors in 13 population-based cancer registries from 1970 through 1996.¹²⁰ The 30-year cumulative incidence of cancer was reported according to age at therapy and sex (Table 105-6). Women treated in their 20s had the highest relative risk compared with an age-matched control population (24.3% vs. 4.5% at 30 years). There was no difference in the incidence of solid tumors in patients treated between 1970 and 1984 and 1985 through 1996, despite the likelihood that patients received more limited doses and fields of RT in the second era. In this study, the relative risk for second solid cancers was also increased after chemotherapy alone, perhaps associated with the increased risk for lung and bladder cancers associated with alkylating agents. A British national cohort study of 5002 women treated with RT for HL reported a standardized incidence ratio of 5 for breast cancer risk and a remarkable SIR of 47 for those treated at age 14 years (Table 105-7).¹²¹ Risk remained high more than 40 years after treatment and decreased with the use of pelvic RT or alkylating chemotherapy likely because of premature menopause. The risk for lung cancer is also substantially increased after both RT and chemotherapy for HL and occurs most commonly in smokers, but not exclusively.¹²² In contrast to breast cancer, an increased risk for lung cancer is seen even in the first 5 years after treatment, especially in those treated with alkylating agents. This difference might suggest a different mechanism for lung cancer induction.¹²³ Smoking increases the risk for lung cancer more than 20-fold in HL survivors and appears multiplicative, not additive, in combination with RT.¹²³

Table 105-6

Second Solid Cancers in 5-Year Hodgkin Lymphoma Survivors*

Age at Diagnosis (yr)	30-Year Cumulative Incidence of Second Cancer
	-HL	-Control	-HL	-Control
20	10.50%	2.40%	24.30%	4.50%
30	18.30%	6.90%	26.10%	8.90%
40	27.10%	17.40%	26.70%	15.40%

^*Study included 18,862 5-year Hodgkin lymphoma survivors in 13 population-based registries.

From Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol 2007;25:1489–97.

Reducing the dose and field of RT and eliminating alkylating agents from primary therapy will likely result in fewer second cancers, but it not clear that there is a “safe and effective” dose of RT. The Childhood Cancer Survivor study showed a clear dose-response relationship between dose of RT to the breast and the odds ratio of breast cancer.¹²⁴ Retrospective analysis of pediatric HL survivors treated with doses of 15 to 25.5 Gy with optional 10-Gy boosts to bulky sites, showed a standardized incidence ratio of 22.9 for second cancers with a cumulative incidence of 17% at 20 years.¹²⁵ Breast cancer risk was substantially decreased with the use of mediastinal versus mantle-field RT and with IFRT compared with EFRT.^28,29 The incidence of lung cancer also appears to follow a dose-response relationship.¹²³ In contrast, the German Hodgkin Study Group HD10 trial, which compared limited chemotherapy combined with 20 or 30 Gy IFRT in favorable early-stage HL, reported a 4.6% incidence of second malignancy at a median follow-up of 7.5 years with no difference in the incidence of second malignancies or deaths from second cancers in those receiving 20 versus 30 Gy.³¹ Recent genome-wide association studies in HL survivors have investigated variants that may be associated with RT-induced second cancers. Allelic variants implicate PRDM1 and FGFR2 in the etiology of second cancer after RT for HL.^126,127 The FGFR2 genotype was specifically studied in RT-induced breast cancer risk, whereas PRDM1 variants were studied in all second cancers. Susceptibility to RT-induced cancers may represent a polygenic trait, with cumulative risk established by co-inheritance of multiple low or intermediate penetrance “risk” alleles.¹¹⁹ Future tests may be available for HL patients to determine their genetic susceptibility to RT-induced cancers, possibly influencing the decision to include RT in the treatment of each patient.

Detailed outcomes for patients with second cancers are difficult to investigate. Breast cancer after RT for HL is more likely to be early stage and bilateral and to be diagnosed by screening when compared with sporadic breast cancer.¹²⁸ HL survivors had a breast cancer–specific mortality similar to matched controls with sporadic breast cancer, but a marked increased risk for a contralateral breast cancer (HR 4.3) and death from any cause. Bilateral mastectomy should be considered in all patients with a diagnosis of breast cancer in the setting of RT for HL.¹²⁸ Compared with patients with de novo non–small cell lung cancer, HL survivors experienced a 30% to 60% decrease in OS after a lung cancer diagnosis.¹²⁹

Cardiovascular and Cerebrovascular Complications

Compared with population-based reference rates, Aleman and associates reported a twofold to sevenfold increased risk for myocardial infarction (MI), angina, congestive heart failure (CHF), and valvular disorders in HL survivors treated with mediastinal RT.¹³⁰ Anthracyclines significantly added to the risk for CHF and valvular disorders, with a 25-year cumulative incidence of CHF after mediastinal RT and anthracyclines of 7.9%. Swerdlow and colleagues found a standardized mortality ratio (SMR) of 2.5 for fatal MI in HL survivors. Risks were independently increased for patients treated with RT, anthracyclines, or vincristine.¹³¹ Risk was particularly high for patients receiving ABVD chemotherapy (SMR 9.5), including those who received ABVD but no mediastinal RT (SMR 7.8).¹³¹ Hodgson and associates showed a significant increase in cardiac-related hospitalizations in patients treated with ABVD alone compared with the general population, with a 10-year risk for cardiac-related hospitalization of 5.5% compared with 2.2% expected in the general population.¹³² After a median follow-up of 14.7 years for 1279 patients treated with mediastinal RT, the 10- and 20-year cumulative incidence of cardiac events were 4.5% and 16%, respectively.¹³³ The standardized incidence ratio of stroke in patients treated with neck and mediastinal RT was 2.5 with a 30-year cumulative incidence of stroke or transient ischemic attack of 7% and a median time from RT to stroke of 17.4 years.¹³⁴ There was a twofold higher risk for those with cardiac disease and an increased risk in patients with hypertension, diabetes, or hypercholesterolemia, supporting recommendations discussed later for aggressive treatment of co-existing cardiovascular risk factors in this population.

Fertility

Because many patients diagnosed with HL are young, maintaining fertility is important in this patient population. Treatment with nonalkyators, such as the ABVD regimen, is considered nonsterilizing.¹³⁵ ABVD induces transient azoospermia in approximately one third of male patients, but most recover within 12 months. Premature ovarian insufficiency after treatment with ABVD is very rare. In contrast, patients treated with alkylator-based regimens, including escBEACOPP, are at significant risk for infertility. As mentioned previously, use of escBEACOPP results in azoospermia and infertility in the majority of male patients and induces premature menopause in 40% of women younger than 30 years and 70% of women 30 years of age or older.^54–54 Conflicting reports regarding the use of oral contraceptives and GnRH to protect the ovarian follicle pool during treatment with alkylators have been published.⁵⁶ Before initiating therapy for HL, all male patients should be offered cryopreservation and banking of sperm, because this process is noninvasive and effective. Consult with a fertility expert is usually not necessary for young female patients receiving only ABVD, but those who will be treated with alkylators (including escBEACOPP), RT below the diaphragm, or SCT should be referred. Options for fertility preservation include co-treatment with a GnRH analog (protective effects remain unclear) and cryopreservation of embryos, oocytes, or ovarian tissue. Cryopreservation of embryos is the most established and reliable method, but the patient must have a partner or use donor sperm and there must be a treatment delay to allow for controlled ovarian stimulation. After any treatment of HL, patients are strongly encouraged to delay childbearing for at least 2 years, because this is the highest risk period for recurrence.

Screening Recommendations

Unfortunately, screening recommendations for second malignancies and cardiovascular disease are necessarily vague because of the small patient numbers and inability to confirm the benefit of screening. In general, all cancer survivors should follow applicable national guidelines for cancer screening such as those provided by the American Cancer Society, American Society of Clinical Oncology, National Comprehensive Care Network, and the U.S. Preventative Services Task Force.136,137 Evaluations of the risk for a second malignancy in HL survivors should also take into account family history, details of the treatment, environmental factors such as smoking, and co-morbid conditions, particularly diabetes, hypertension, and hypercholesterolemia. Annual breast screening is recommended in all women treated with mediastinal or axillary RT beginning 7 to 10 years after treatment; and in those treated between ages 10 years and 30 years, an annual breast magnetic resonance imaging should be done in conjunction with an annual mammogram.^138,139 HL survivors who are current or former smokers and were treated with RT or alkylating agents should consider annual low-dose spiral chest CT starting 5 years after treatment for patients receiving alkylating agents and 10 years after treatment for patients who received supradiaphragmatic RT.¹³⁷

Screening for cardiovascular disease should include a lipid panel every 3 years with statin therapy recommended for those with a low-density lipoprotein cholesterol value higher than 100, a fasting glucose level checked every 2 to 3 years, annual blood pressure monitoring, and an initial cardiac stress test 5 to 10 years after therapy with continued periodic monitoring.30,140–142 Carotid Doppler imaging is unlikely to be useful as screening for cerebrovascular disease based on the very low incidence of significant stenosis in HL survivors suffering a cerebrovascular accident.¹³⁴ Patient education, counseling, and surveillance for late complications are essential aspects of life-long follow-up care for HL survivors.