Hodgkin Lymphoma

Hodgkin Lymphoma

102 

Nancy Bartlett and Grace Triska

S UMMARY

OF

K EY

P OI NT S

Incidence

• There were an estimated 8260 new cases of Hodgkin lymphoma (HL) in the United States in 2017 with 1070 deaths. • The US age-adjusted incidence rate is 2.6 per 100,000 per year. • There is a higher incidence among males than females. • The highest incidence is in North America and Western Europe. • There is a bimodal age distribution (peaks at 15–35 years and then again later in life).

Biologic Characteristics

• Hodgkin Reed-Sternberg (HRS) and lymphocyte-predominant (LP) cells derive from germinal center B-cells. HRS and LP cells are rare in the lymphoma tissue, and interactions with other cells in the microenvironment may play a role in the pathophysiology of the disease. • In classical HL (cHL), HRS cells express CD30+ and have lost expression of B-cell markers. • Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) represents a distinct clinicopathologic entity characterized by scattered large “popcorn” cells that express CD45 and CD20. • Epstein-Barr virus may be involved in the pathogenesis of some cHL cases, particularly in tropical areas. • Programmed cell death-ligand 1 (PD-L1) and PD-L2 overexpression is a defining feature of cHL and suggests the potential success of checkpoint blockade as therapy.

Staging Evaluation

• Physical examination with attention to peripheral nodes and the spleen. Cervical, supraclavicular, and mediastinal nodes are involved in the majority of patients with cHL.

• History includes the presence or absence of pruritus, drenching night sweats, fevers, and significant weight loss. • Laboratory evaluation should include a complete blood count with differential, albumin, and erythrocyte sedimentation rate. • Positron emission computed tomography/computed tomography (PET/CT) scan is also used in the diagnosis. • Bone marrow biopsy is not indicated in early-stage disease and may no longer be needed in advanced-stage disease in patients having a PET scan.

Primary Therapy

• Early-stage nonbulky cHL: ○ Three to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone results in equivalent overall survival, modestly inferior progression-free survival, and less long-term toxicity than combined-modality therapy. ○ ABVD chemotherapy (2 to 4 cycles) is given with 20 to 30 Gy of involved-field radiotherapy (IFRT) with the number of cycles and dose of radiotherapy (RT) dictated by high-risk features. ○ Interim PET is likely to select patients who benefit most from RT. ○ Consider changing therapy to escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) for 2 cycles followed by consolidative RT in patients with positive interim PET.

• Early-stage cHL with bulky disease: ○ Combined-modality therapy uses 4 to 6 cycles of ABVD followed by IFRT. ○ In patients with negative interim PET results after 2 cycles of ABVD, 6 cycles of ABVD without RT is acceptable. ○ In patients with positive interim PET results after 2 cycles of ABVD, consider changing therapy to escalated BEACOPP for 2 to 4 cycles before consolidative RT. ○ Reduced radiation doses or therapy with limited RT fields should be considered, especially for younger patients who have a significantly higher risk of developing breast cancer, lung cancer, or cardiovascular disease. • Advanced-stage cHL: ○ Standard risk: 6 cycles of ABVD. ○ High risk: 6 cycles of ABVD or escalated BEACOPP. ○ Interim negative PET results after 2 cycles of ABVD: Omit bleomycin during cycles 3 to 6 of ABVD. ○ Interim positive PET results after 2 cycles of ABVD: Consider changing therapy to escalated BEACOPP or alternative salvage regimen. • Limited-stage NLPHL: ○ Observation after resection of solitary involved node. ○ IFRT. ○ Combined-modality therapy with 2 to 4 cycles of rituximab + chemotherapy plus IFRT. ○ Rituximab + chemotherapy for stage II patients with noncontiguous sites of involvement. • Advanced-stage NLPHL: ○ R-CHOP (rituximab + cyclophosphamide, vincristine, prednisone). Continued

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1912 Part III: Specific Malignancies

Salvage Therapy

• Salvage chemotherapy followed by autologous stem cell transplant is the standard approach, with 50% to 60% of patients achieving long-term remissions.

• Pretransplant PET/CT highly predictive of outcomes. • Brentuximab vedotin, an antibody– drug conjugate, has a 75% response rate in relapsed or refractory HL.

INTRODUCTION Nearly 90% of patients with early-stage Hodgkin lymphoma (HL) and 80% of patients with advanced-stage HL will be cured. Survival rates have improved as a result of enhanced diagnostic techniques, better staging methods, maintaining chemotherapy dose intensity, more effective salvage regimens, and perhaps a greater appreciation of the need to screen for late complications, with the potential for superior outcomes with early intervention of cardiovascular disease and second cancers. Although indirect evidence, including populationbased findings of improved survivals since 1980, provides credence to the idea that limiting the number of cycles of chemotherapy and decreasing the use of radiotherapy (RT) has not resulted in worse overall outcomes for patients with HL and supports increasing efforts to minimize therapy in low-risk patients in an effort to minimize late toxicities.1,2 With new biologic prognostic markers and novel drugs for HL recently approved and under development, outcomes are likely to continue to improve.

EPIDEMIOLOGY AND ETIOLOGY In the United States, it was estimated that 8260 new cases of HL would be diagnosed in 2017 with 1070 deaths.3 The US age-standardized incidence rate (ASR) per 100,000 per year is 2.6, with higher incidence among males. The median age at diagnosis is 39 years, and there is a bimodal age distribution in resource-rich countries, showing peaks at 15 to 35 years and then later in life. Worldwide, the incidence of HL is highest in Europe (ASR, 2.0), the Americas (ASR, 1.5), and the eastern Mediterranean (ASR, 1.5).4 Regions with lower ASRs include Africa (ASR, 0.7), South-East Asia (ASR, 0.6), and the western Pacific (ASR, 0.2). In the United States, ASRs vary among races and ethnicities with the highest incidence in non-Hispanic whites (ASR, 3.1 for males and 2.4 for females) followed by blacks (ASR, 3.1 for males and 2.2 for females).3 The incidence rates have remained stable for whites, blacks, and Hispanics but nearly doubled between 1992 and 2007 for Asians and Pacific Islanders.5 US-born Asians and Pacific Islanders and US-born Hispanics had a higher incidence of HL than foreign-born Asians and Pacific Islanders and Hispanics, supporting an environmental component. Epidemiologic studies support both environmental and genetic factors in the etiology of HL. Multiple siblings, higher birth order, crowded living conditions, lower socioeconomic status, and exposure to daycare have all been associated with a decreased risk of HL in young adults. Historically, this has been interpreted as evidence to support late exposure to an infectious agent as an etiologic factor in the development of HL, but no causal virus has been found. Additional circumstances associated with an increased risk of HL include a lower level of fecal–oral exposure early in life (e.g., lower incidence in thumb suckers), appendectomy, tonsillectomy, eczema, and smoking.6 As opposed to a specific etiologic infectious agent, others have proposed the “hygiene hypothesis” as a potential cause of young adult HL. This theory proposes that a reduction in cumulative microbial exposures in childhood may adversely affect immune response development, specifically decrease interleukin (IL)-12 secretion, leading to persistence of the T-helper type 2 phenotype, resulting in an immature immune response phenotype.6,7

• Nivolumab and pembrolizumab, PD-1 inhibitors, have a 65% overall response rate in relapsed or refractory HL.

Epstein-Barr virus (EBV) has long been thought to play a role in the pathogenesis of a subset of HL cases because EBV latent membrane protein or EBV-encoded small RNAs (EBER) is found in Hodgkin Reed-Sternberg (HRS) cells in approximately one-third of HL cases. Serum profiles of antibodies to EBV are significantly altered, both before and after the diagnosis of EBV-positive classical Hodgkin lymphoma (cHL).8,9 These distinctive serologic responses to EBV latent antigens are also seen in other disorders associated with immune dysfunction such as AIDS, rheumatoid arthritis, and inherited immunologic disorders.8 In young adults, a history of infectious mononucleosis is a risk factor for EBV-positive cHL in some series, occurring at a median of 2.9 years after infectious mononucleosis infection.10 Support is building for a familial or inherited component in the development of HL. Mack and coworkers’ landmark study of twins revealed that monozygotic but not dizygotic twins of patients with HL had a significant increased risk of developing HL.11 In a study of 57,475 first-degree relatives of 13,922 HL patients, first-degree relatives of cHL patients had a 3-fold increased risk for developing cHL.12 The risk of cHL was 6-fold in siblings compared with 2.1-fold in parents or children, with a higher risk in sisters (9.4-fold) than in brothers (4.5-fold) or opposite-sex siblings (5.9-fold). There was a 13-fold increased risk in those with multiple first-degree relatives affected by HL. The risk of cHL in same-sex twins was 57-fold. This increased risk of HL in relatives inspired genomic studies of cHL, specifically investigating the major histocompatibility complex (MHC) region (human leukocyte antigen system [HLA]). The HLA class I region is associated with EBV-positive HL in numerous studies, with many focusing on the HLA-A gene. Niens and coworkers reported that the HLA-A*01 haplotype was associated with an increased risk of developing EBV-positive HL, but the HLA-A*02 haplotype was associated with a decreased risk.13 These associations were confirmed in the presence of infectious mononucleosis; the authors suggested that the association between a history of infectious mononucleosis and EBV-positive lymphoma was not seen in the presence of HLA-A*02 because this allele appeared to “neutralize the effect of infectious mononucleosis.”14 In a genome-wide association study of cHL and EBV, the associations of the class I region variants with EBV-positive cHL and class II region variants with EBV-negative cHL were corroborated.15 Additionally, two loci in the MHC region were associated with cHL, irrespective of EBV status. This suggests that there may be some components of pathogenesis that are common to both EBVnegative and EBV-positive cHL. Huang and coworkers studied HLA and EBV using a polymerase chain reaction–based sequence-specific oligonucleotide probe hybridization approach and discovered significant differences between EBV-positive and EBV-negative cHL cases for several probes that discriminate between HLA-A*01 and HLA-A*02.16 The authors concluded that these HLA antigens are responsible for the association of EBV with HL, not specific single nucleotide variants shared by multiple alleles. Johnson and coworkers confirmed the association of HLA-A*01.01 and B*37:01 with an increased risk of EBV-positive HL but also described two alleles, DRB1*15:01 and DPB1*01:01, associated with a decreased risk.17 The class II single nucleotide polymorphism rs6903608 was the strongest predictor of EBV-negative HL. In summary, epidemiology and genetic studies lend support to both environmental and genetic influences in the development of HL. Is

Hodgkin Lymphoma  •  CHAPTER 102 1913

the altered immune response to pathogens noted in many HL studies cause or effect? If the altered immune response is etiologic, is it genetic or environmental in origin? The demographics of HL, with a bimodal age distribution, support multiple etiologies. Importantly, none of these epidemiology studies shed light on the actual pathogenesis of HL. How do any of the potential etiologic factors result in transformation of a germinal center (GC) B-cell to a malignant HRS cell?

PATHOLOGY AND BIOLOGY Hodgkin lymphoma is subclassified into cHL, which comprises 95% of all cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) based on distinct immunophenotypes. Classical HL subtypes include nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted. Although the differentiation between cHL and NLPHL is critical for the determination of treatment and prognosis, the precise subtype of cHL is rarely clinically relevant. In cHL, rare, scattered mononuclear (Hodgkin) and multinucleated (Reed-Sternberg) cells are found in a mixture of inflammatory and accessory cells such as eosinophils, neutrophils, histiocytes, plasma cells, and fibroblasts (Fig. 102.1 A and B). T lymphocytes often ring the HRS cells in a rosette-like manner. HRS cells are uniformly positive for CD30 and frequently positive for CD15, both in a membrane pattern with Golgi staining (Fig. 102.1C). CD20 expression is variable, MUM1 staining is positive, and PAX5 staining is weaker in HRS cells than in reactive B-cells. The cells are usually negative for CD45.

The detection of EBV-encoded RNA is indicative of cHL and is found in approximately one-third of cases. NLPHL is composed of numerous large, tightly packed nodules (Fig. 102.1D). Scattered large “popcorn” or lymphocyte-predominant (LP) cells are positive for CD20 but rarely positive for CD15 or CD30. These LP cells are present with normal lymphocytes and histiocytes within large spherical meshworks of the follicular dendritic network. If the process is entirely diffuse, the diagnosis of T cell–rich large B-cell lymphoma must be considered. Both LP and HRS cells are derived from GC B-cells.18 LP cells express several typical GC B-cell markers and grow in a follicular dendritic network. In contrast, HRS cells have lost their B-cell signature through transcriptional reprogramming, likely by DNA methylation, upregulation of NOTCH1 and other negative regulators of B-cells, and the persistent activation of nuclear factor–κB (NF-κB).18 HRS cells, which cannot produce immunoglobulins, should be targeted for apoptosis, but NF-κB is involved in the protection of these cells. This NF-κB protection can result from EBV infection, and these infected cells are then independent of the normal B-cell receptor survival signals.19 Other pathways with deregulated activation in HRS cells include JAK (Janus kinase)/STAT (signal transducer and activator of transcription), phosphoinoside-3-kinase (PI3K)/Akt, Activator protein-1 (AP-1), and MAPK (mitogen-activated protein kinase)/Erk.18,20 Tiacci and coworkers21 reported the first genome-wide transcriptional analysis of microdissected HRS cells compared with cHL cell lines and normal B-cell subsets.21 This analysis identified two molecular subgroups of cHL

A

B

C

D

Figure 102.1  •  Histology and immunohistochemistry of Hodgkin lymphoma (HL). (A) Classic Reed-Sternberg cell, demonstrating large size, multinucleated nucleus, and prominent eosinophilic nucleolus. (B) The majority of cells in classical HL are nonmalignant and consist of a supportive environment that includes lymphocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. (C) Classical HL expresses CD30, a marker of activated B- and T-lymphoid cells, in almost all cases. (D) Nodular lymphocyte-predominant HL has distinctive surface markers and morphologic features, including numerous, tightly packed nodules at low power.

1914 Part III: Specific Malignancies

with varying strengths of NOTCH1, MYC, and IRF4 proto-oncogenes. Additionally, BIK (apoptosis inducer) and INPP5D (inhibitor of PI3K pathway) were silenced in HRS cells. Genome sequencing and mutation analysis of HL have trailed other tumors because of the rarity of HRS in biopsy samples. Investigators have overcome some of the challenges by using flow-sorted HRS and intratumor T-cells. Reichel and coworkers used whole-exome sequencing on 10 primary cHL samples to reveal that β2-microglobulin (B2M) and TNFAIP3 were the most commonly mutated genes in HRS cells.22 Interestingly, all 7 nodular sclerosis cHL cases had mutations in B2M, and 6 of these 7 had mutations in TNFAIP3. In the expanded cohort, 86 of 115 (75%) nodular sclerosis cHL cases showed B2M inactivation, but only 9 of 40 (22%) mixed cellularity cHL cases showed B2M inactivation. Fluorescent in situ hybridization (FISH) assays reveal chromosome 9p.24.1/PD-L1/PD-L2 alterations are present in nearly all cases of cHL and result in increased expression of programmed cell death (PD)-1 ligands.23 In one study examining 9p24.1 by FISH, in samples from 108 patients with cHL, copy number gain (56%), and amplification (36%) of the PDL1 and PDL2 loci were concordant in 97% of patients. Progression-free survival (PFS) was significantly worse for patients with amplification, which was more common in advanced stage.23 These alterations likely explain the encouraging activity of checkpoint inhibitors, such as nivolumab and pembrolizumab, in patients with cHL. The tumor microenvironment is critical in the development and proliferation of HL. Reactive cells assist in the proliferation of HRS cells by secreting chemokines and cytokines and creating an immunosuppressive environment. Chetaille and coworkers used gene expression profiles generated using DNA microarrays to show variations in the tumor environment correlate with outcome.24 Altered cytokines, chemokines, receptors, and ligands contribute to cHL pathogenesis by promoting T helper (Th) 2 cell response (TARC/CCL17, MDC/ CCL22, CCL-20, MIG, IP-10, IL-13, GATA-3, CCR-4); suppressing Th1 response (IL-10, transforming growth factor–β [TGF-β], PD-1L, galectin-1); and promoting the influx of eosinophils (IL-5, IL-9, eotaxin, CCL28), mast cells (IL-9, RANTES [regulated on activation, normal T-cell expressed and secreted]/CCL5), plasma cells (IL-6), neutrophils (IL-8, granulocyte-macrophage colony-stimulating factor [GM-CSF]), and fibroblasts (IL-13, TGF-β, TNF-α, matrix metalloproteinase [MMP], tissue inhibitor of metalloproteinase [TIMP] 1, TIMP2).25 Interactions with CD4+ T-cells, a mixture of Th cells and regulatory T-cells that surround the HRS cell, appear to play a critical role in HRS cell survival.20

CLINICAL MANIFESTATIONS, EVALUATION, AND STAGING Common presenting symptoms include painless peripheral adenopathy most commonly in the cervical or supraclavicular region, cough or chest pain related to mediastinal disease, and pruritus. B symptoms, including recurrent drenching night sweats, recurrent unexplained fever greater than 38°C, and unexplained weight loss (>10% of baseline) occur in about 40% of patients. Bulky mediastinal disease is most common in young women with nodular sclerosis cHL (Fig. 102.2). Mixed-cellularity cHL more often presents in older men as peripheral adenopathy or subdiaphragmatic involvement and rarely mediastinal involvement. Lymphocyte-rich cHL usually has a very favorable presentation with nonbulky peripheral adenopathy. Lymphocyte-depleted cHL usually presents at advanced stage (III–IV) with retroperitoneal lymph node, abdominal organs, and bone marrow involvement. NLPHL patients usually present with limited-stage disease with cervical, axillary, or inguinal lymph node involvement. Staging of HL is based on the Ann Arbor staging system with the “Cotswolds” modifications. Four stages document the extent of lymph node and disseminated disease (Table 102.1) with information on the presence (B) or absence (A) of B symptoms. Additionally, contiguous

Figure 102.2  •  Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography scan in a patient with Hodgkin lymphoma demonstrating a large mediastinal mass with a mediastinal mass ratio of 0.54. Table 102.1  Modified Ann Arbor Staging System

for Hodgkin Lymphoma

Stage

Involvement

I II

Single lymph node region (I) or one extralymphatic site (IE)a Two or more lymph node regions, same side of the diaphragm (II) or local extralymphatic extension plus one or more lymph node regions or same side of the diaphragm (IIE)a Lymph node regions on both sides of the diaphragm (III), which may be accompanied by local extralymphatic extension (IIIE)a Diffuse involvement of one or more extralymphatic organs or sites No B symptoms Presence of at least one of the following symptoms: 1. Unexplained weight loss >10% baseline during 6 months before staging 2. Recurrent unexplained fever >38°C 3. Recurrent night sweats Bulky tumorb

III

IV  A  B

a E lesion: Localized extranodal extension of Hodgkin lymphoma from a contiguous or nearby nodal site is noted with the designation E, for example, stage IIEA for asymptomatic disease in the mediastinum with contiguous extension into nearby lung. b Bulky tumor is defined as either a single mass of tumor tissue exceeding 10 cm in largest diameter or a mediastinal mass exceeding one third of the maximum transverse transthoracic diameter measured to the inside of the ribs on a standard posteroanterior chest radiograph. Data from Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31:1860–1861.

extranodal involvement is designated E and bulky disease, designated as X, defined as either a single mass larger than 10 cm or a mediastinal mass exceeding one-third of the maximum transverse transthoracic diameter measured to the inside of the ribs on a standard posteroanterior chest radiograph, is noted. Stage I HL involves a single nodal region, stage II HL involves two or more lymph node regions on the same

Hodgkin Lymphoma  •  CHAPTER 102 1915

Table 102.2  Prognostic Factors in Hodgkin Lymphoma EARLY STAGE

ADVANCED STAGE

Risk Factors

European Organization for Research and Treatment of Cancer

German Hodgkin Study Group

Bulk Sites Laboratory

MMR >1/3 >3 nodal sites ESR ≥50 (if asymptomatic)

MMR >1/3 >2 nodal sites ESR ≥50 (if asymptomatic)

ESR ≥30 (if symptomatic)

ESR ≥30 (if symptomatic)

Age ≥50 yr

—

Demographics

Hasenclever — Stage IV Hemoglobin <10.5 g/dL WBCs ≥15,000/µL Lymphocytes <600/µL or <8% of WBCs Albumin <4 g/dL Age ≥45 yr Male gender

ESR, Erythrocyte sedimentation rate; MMR, mediastinal mass ratio; WBC, white blood cell.

side of the diaphragm, stage III HL involves lymph node regions on both sides of the diaphragm, and stage IV HL diffusely involves one or more extralymphatic organs or sites. Patients should have an excisional biopsy if possible. Although core needle biopsies provide limited tissue in which to examine rare HRS cells and architecture and flow cytometry does not contribute to HL diagnosis, there are cases where large core needle biopsies may be adequate. Pretreatment evaluation should include physical examination and history, laboratory studies (complete blood count, chemistries, erythrocyte sedimentation rate [ESR]), and whole-body positron emission computed tomography/computed tomography (PET/CT). Limited-stage HL is more common with approximately 25% of patients presenting with stage I, 40% with stage II, 20% with stage III, and 15% with stage IV.3 In addition to determining stage at diagnosis, patients should be classified by International Prognostic Score (IPS) risk group if advanced stage and as unfavorable or favorable according to the German Hodgkin Study Group or European Organization for Research and Treatment of Cancer criteria if limited stage (Table 102.2). Risk factor classification provides prognostic information and helps with treatment stratification. At workshops in 2011 and 2013, an International Working Group met to develop improved staging and response criteria of HL and non-Hodgkin lymphoma (NHL).26 The revised response criteria included PET/CT in the standard staging of all fluorine-18 fluorodeoxyglucose (FDG)–avid lymphomas. PET/CT scans are strongly encouraged in HL for staging, interim response assessment, and to establish remission. Traditionally, bone marrow biopsy has been recommended for patients with advanced disease. El-Galaly and coworkers reported on 454 patients with newly diagnosed HL of whom 18% had focal skeletal lesions on PET/CT and 6% had positive bone marrow biopsy.27 No patients with stage I or II HL had positive bone marrow biopsy results, and no patients were allocated to a higher clinical risk group based on bone marrow biopsy. Of 27 patients with bone marrow involvement, 23 (85%) had focal bone lesions on PET/ CT. Diffuse marrow uptake was never associated with a positive bone marrow biopsy. PET/CT had a negative predictive value of 99% for bone marrow involvement. Bone marrow biopsy is unlikely to change the risk or treatment strategy in the age of PET/CT staging and can likely be eliminated in all patients.

PRIMARY THERAPY Despite the overall excellent prognosis of the majority of patients with HL, debate continues as to the optimal initial treatment for both early- and advanced-stage disease. Because of the unique efficacy of salvage therapy for HL, a slightly less effective but less toxic approach as initial therapy may ultimately optimize survivorship.28 Based on compelling data from Gallamini and coworkers showing a 2-year PFS

of 12% for HL patients with a positive PET scan after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) compared with 95% for patients with negative interim PET results, the use of interim PET has become widespread in standard practice and is the focus of recent clinical trials in both early and advanced HL.29 Tailoring therapy based on results of an interim PET/CT scan performed after 1 to 3 cycles of chemotherapy may represent the optimal approach for most patients.

Early-Stage Nonbulky Hodgkin Lymphoma The transition from extended-field radiotherapy (EFRT) to combinedmodality therapy with chemotherapy and involved-field radiotherapy (IFRT) in the 1990s represented a major step forward in the treatment of limited stage HL.30,31 Because of concerns of serious late toxicities (described in detail in Late Complications of Therapy section), there is universal agreement that the dose and field of radiation should be minimized in the treatment of early-stage HL. De Bruin and coworkers 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 coworkers showed a marked decrease in second cancers in patients receiving IFRT compared with EFRT.32,33 However, because mediastinal nodes are involved in the majority of patients with HL, most patients undergoing RT for HL continue to have at least modest exposure to the heart, lungs, and breasts regardless of efforts to administer only involved-site RT. The 2012 publication of a randomized trial of ABVD 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 PFS, confirms the need to consider both efficacy and late toxicity in treatment decisions.28 Current guidelines and recommendations continue to support either chemotherapy alone or combined modality therapy in the treatment of nonbulky early-stage HL.34 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, 2 cycles of ABVD and 20 Gy of IFRT resulted in a 5-year freedom from treatment failure (FFTF) of 91% and overall survival (OS) of 97%.35 There was no advantage to 4 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 below 50 mm/hr if no B symptoms and above 30 mm/hr in the presence of B symptoms. Early-stage patients not meeting the eligibility criteria for HD10 were treated on the HD11 trial comparing 4 cycles of ABVD with 4 cycles of standard-dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

1916 Part III: Specific Malignancies

100 Recurrent Hodgkin lymphoma Second malignant condition Cardiovascular events

30

20

10

0 0

5

10

15

20

Radiotherapy

90

25

30

Years

Figure 102.3  •  Approximate cumulative risk of Hodgkin lymphoma (HL), second malignancies, and cardiovascular events among patients receiving combined modality therapy for early-stage HL. (Adapted from Armitage JO. Early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):653–662.)

Progression-free survival (%)

Cumulative occurrence (%)

40

80

No further treatment

70 60 50 40 30 20

Rate ratio, 1.57 (95% CI, 0.84−2.97) P = .16

10 0 0

12

24

36

48

60

72

84

96 108 120

Months since randomization

Figure 102.4  •  Progression-free survival. CI, Confidence interval. (Adapted

followed by 20 or 30 Gy IFRT.36 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 4 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.28,37 However, with a follow-up duration of 4 to 5 years, no trial comparing chemotherapy alone with 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 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 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. 102.3).38 Critics condemn this study because of 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 compares favorably with the 5 to 8-year EFS rates of 86% to 87% reported in the HD10 and HD 11 trials of ABVD in combination with limited dose and field RT. Two large phase 3 studies explored the use of interim PET to guide decisions regarding chemotherapy intensity and consolidative RT in early-stage nonbulky cHL. The UK RAPID (Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease) trial included patients with nonbulky HL without regard to other risk factors.39 All patients received 3 cycles of ABVD and were restaged with a PET/CT scan. Patients with a negative PET result, as defined by a score of 1 or 2 on the Deauville visual analog scale, were then randomized to receive IFRT versus observation. Patients with a positive interim PET went on to receive 1 additional cycle of ABVD followed by IFRT. In this study, 74.6% of patients had a negative PET scan after 3 cycles of ABVD. With a median follow-up of 60 months, 90.5% of interim PET negative patients (380 of 420) and 87.6% of interim PET-positive patients (127 of 145) are alive and progression free. The 3-year PFS and OS

from Radford J, Illidge T, Counsell N, et al. RAPID trial Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med. 2015;372(17):1598–1607.)

rates were 94.6% and 97.1%, respectively, in the PET-negative patients randomized to IFRT compared with 90.8% and 99%, respectively, in the PET-negative patients randomized to no further treatment (Fig. 102.4). The confidence intervals (CIs) of the absolute risk difference of -3.8% (95% CI -8.8, 1.3%) in PFS marginally exceeded the acceptable noninferiority margin of -7%. Ideally, longer follow-up of this study will be forthcoming and provide reassurance that OS remains equivalent in the two arms despite a slightly higher rate of recurrence in the observation arm. Most practitioners interpret these results as adequate to recommend chemotherapy alone in the 75% of patients with early negative interim PET/CT. The European Organisation for Research and Treatment of Cancer (EORTC) H10 trial accrued 1950 patients with early-stage HL with 754 categorized as favorable and 1196 as unfavorable based on the criteria listed in Table 102.2.40 Patients were randomly assigned to a standard therapy arm with 3 or 4 cycles of ABVD and INRT (involved nodal radiation therapy) versus the experimental arm in which patients with a negative interim PET after 2 cycles of ABVD received 2 (favorable) or 4 (unfavorable) additional cycles of ABVD without RT and patients with a positive interim PET changed therapy to 2 cycles of escalated BEACOPP (escBEACOPP) and INRT. For the 18.8% of patients (13.3% favorable and 22.4% unfavorable) with a positive interim PET (uptake greater than blood pool) after 2 cycles of ABVD, the 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to 2 cycles of escBEACOPP + INRT (hazard ratio [HR], 0.42; P = 0.002). There was also a trend in the PET-positive group toward improved 5-year OS in the experimental arm (96% versus 89%, P = .062; H,R 0.45). In patients with a negative interim PET, the difference in 5-year PFS between the standard 3 or 4 cycles of ABVD + INRT and the experimental arm with 4 to 6 cycles of ABVD were most marked in the favorable group but favored INRT in both groups (99% versus 87.1%; HR, 15.8 in the favorable group and 92.1% versus 89.6%; HR, 1.45 in the unfavorable group) (Fig. 102.5). There was no difference in OS with more than 96% of patients with an interim negative PET result alive at 5 years in both arms. Without a difference in OS at 5 years and continued concern about late effects that may ultimately impact OS, chemotherapy alone remains a reasonable approach in patients with a negative interim PET result; however, in those with a positive interim PET result, more intensive chemotherapy and INRT are warranted.

A

100

100

90

90

Progression-free survival (%)

Progression-free survival (%)

Hodgkin Lymphoma  •  CHAPTER 102 1917

80 70 60 50 40 30 20 10

HR, 15.8 (95% CI, 3.75−66.07)

0

1

2

3

4

5

6

7

8

B

80 70 60 50 40 30 20 10 0

HR, 1.45 (95% CI, 0.84−2.50) 1

2

3

227 238

223 228

221 214

216 198

5

6

7

8

Time (yr)

Time (yr) O Patients (n) Patients at risk (n) 2 31

4

O Patients (n) Patients at risk (n) 203 177

112 105

25 29

2 2

ABVD + INRT 22 ABVD only 32

292 302

284 282

277 266

265 261

246 242

147 145

35 36

3 2

ABVD + INRT ABVD only

Figure 102.5  •  Progression-free survival for positron emission tomography–negative patients with early-stage Hodgkin lymphoma treated with chemotherapy

alone versus combined modality therapy. Shown are the rates of progression-free survival of the (A) favorable (F) groups of patients randomly assigned to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + involved-node radiotherapy (INRT; n = 227) or ABVD only (n = 238) and of the (B) unfavorable (U) groups randomly assigned to ABVD + INRT (n = 292) or ABVD only (n = 302). CI, Confidence interval; HR, hazard ratio, O, observed. (Adapted from André MPE, Girinsky T, Federico M, et al. Early positron emission tomography response–adapted treatment in stage I and II Hodgkin Lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017;35(16):1786–1794.)

Early-Stage Bulky Hodgkin Lymphoma The standard treatment for patients presenting with early-stage bulky HL has historically been combined-modality therapy.31,38 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. The phase 3 intergroup trial E2496 enrolled 268 patients with stage I or II bulky disease.41 The patients were treated with ABVD plus modified IFRT to 36 Gy for patients with bulky mediastinal disease or Stanford V plus modified IFRT to 36 Gy for sites larger than 5 cm in maximum transverse dimension. In patients with bulky, early-stage disease, the 5-year FFS and OS were 82% and 94%, respectively, with no difference between 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 only randomized trial addressing the question of RT in bulky limited stage HL was the EORTC H10 trial discussed previously. Approximately 40% of patients (n=375) in the unfavorable arm of this trial had bulky mediastinal disease defined as a mediastinal–thoracic ratio of greater than 0.35.40 For unfavorable patients with a negative interim PET result, the 5-year PFS was 89.6% for 6 cycles of ABVD compared with 92.6% for 4 cycles of ABVD + INRT (HR, 1.45) with a 5-year OS of 98.3% in the chemotherapy alone arm compared with 96.7% in the CMT arm. The phase 3 RATHL (Response-Adapted Therapy in Advanced Hodgkin Lymphoma) study exploring the elimination of bleomycin in patients with advanced-stage disease and negative interim PET results included 119 patients with bulky stage II disease who received no consolidative RT after 6 cycles of ABVD/ AVD and had an encouraging 3-year PFS of 91.5%.42 Additional support for avoiding consolidative RT in patients with bulky early-stage HL who achieve a complete remission with chemotherapy comes from the British Columbia Cancer Agency (BCCA) lymphoma registry.43 Among 102 patients with bulky mediastinal HL and a negative end of treatment PET after 6 cycles of ABVD, the 5-year FFTF was 89% with a 5-year OS of 96% without the use of RT. These three studies

support the approach of chemotherapy alone in early-stage patients with bulky disease and a negative interim or end of treatment PET, with expected cure rates of approximately 90%. Encouragingly, in the EORTC H10 study, patients with unfavorable characteristics, including bulk and a positive interim PET result, had a 3-year PFS of 77.4% with 4 cycles of ABVD + INRT and 90.6% with 2 cycles of ABVD + 2 cycles of escBEACOPP + INRT.40 This is the first study to show that intensifying chemotherapy before consolidative RT in patients with a positive interim PET result significantly decreases relapse rates. Again, the results were not presented independently for the 40% of patients with bulky disease but can likely be extrapolated to this subgroup.

Advanced-Stage Hodgkin Lymphoma The majority of patients with stage III to IV HL receive 6 cycles of ABVD chemotherapy, the standard treatment for nearly 3 decades. The Hasenclever IPS is used to predict prognosis of patients with advanced-stage HL treated with ABVD (see Table 102.2).44 In the original publication, the 5-year freedom from progression (FFP) rates were 70% for those with zero to three risk factors compared with 47% for those with four or more high-risk features. The outcomes of patients with advanced-stage HL treated in British Columbia between 1980 and 2010 according to the IPS (Table 102.3) showed more favorable 5-year PFS rates of 81% for lower risk patients (IPS, 0–3) and 65% for the high-risk patients (IPS, 4–7).45 Several reasons are hypothesized for improved outcomes over time, including improved diagnostic accuracy resulting in elimination of patients with NHL, 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 patients, and anthracycline-based therapy in all patients compared with only 80% of patients in the original series.45–47 The routine use of autologous stem cell transplant (ASCT) in patients with relapsed HL likely accounts for the improvement in OS. Although the IPS continues

1918 Part III: Specific Malignancies

Table 102.3  Five-Year Freedom From Progression

and Overall Survival by International Prognostic Score 5-YEAR FFP

IPS Score 0 1 2 3 4 ≥5

5-YEAR OS

Moccia et al

Hasenclever et al

Moccia et al

Hasenclever et al

88 ± 5 84 ± 3 80 ± 3 74 ± 3 67 ± 5 62 ± 7

84 ± 4 77 ± 3 67 ± 2 60 ± 3 51 ± 4 42 ± 5

98 ± 2 97 ± 1 91 ± 2 88 ± 3 85 ± 4 67 ± 7

89 ± 2 90 ± 2 81 ± 2 78 ± 3 61 ± 4 56 ± 5

FFP, Freedom from progression; IPS, International Prognostic Score; OS, overall survival. Data from Hasenclever et al44 and Moccia et al.45

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 for advanced-stage HL. Initially reported in 2003, a large randomized trial comparing 8 cycles of escBEACOPP to COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABVD showed that escBEACOPP resulted in better tumor control and OS.48 Ten-year follow-up of the trial showed FFTF and OS rates of 64% and 75%, respectively, for COPP/ABVD compared with 82% and 86% for escBEACOPP (P <.0001).49 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. 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.50-54 A randomized trial of 6 versus 8 cycles of escBEACOPP in advancedstage HL showed a more favorable toxicity profile and improved 5-year OS with 6 cycles.55 Secondary AML/MDS (myelodysplastic syndrome) occurred in 0.3% of those receiving 6 cycles compared with 2.7% for 8 cycles, and acute treatment-related deaths were 0.8% with 6 cycles versus 2.1% for 8 cycles. In three other randomized trials of escBEACOPP versus ABVD, escBEACOPP was not associated with a survival advantage despite a lower rate of relapse.56–58 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 4 cycles of escBEACOPP and 2 cycles of standard BEACOPP in two trials and 4 cycles of escBEACOPP and 4 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 of 45) of the patients who failed ABVD remained in continuous complete remission (CR) after salvage therapy compared with only 15% (3 of 20) of the BEACOPP failures at a median follow-up of 61 months.56 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, with the trade-off being that a higher percentage of patients will need salvage therapy, including an ASCT. ASCT is now associated with a less than

2% acute mortality rate in most centers and in many ways may be a more tolerable treatment than 6 cycles of escBEACOPP. As discussed under the treatment of early-stage disease, the interim PET/CT scan may allow us to tailor therapy 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 2 cycles of ABVD (PET-2), only PET-2 was significant in a multivariable analysis that included all IPS factors.29 Still under investigation is whether altering therapy on the basis of the interim PET will result in more favorable outcomes. In a retrospective review of 154 newly diagnosed advanced-stage HL patients treated in 2006 and 2007 at one of nine Italian or US centers, with 2 cycles of ABVD followed by 8 cycles of BEACOPP (4 escalated and 4 standard) if an interim PET/CT scan was positive, and an additional 4 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).59 These results are in stark contrast to the 2-year PFS of 12% reported by Gallamini and coworkers for patients with a positive interim PET/CT results who continue treatment with ABVD.29 Similar results were reported in the US Intergroup S0816 trial, which enrolled 336 patients with newly diagnosed stage III to IV HL and treated all patients with 2 cycles of ABVD followed by an interim PET scan.60 The 82% of patients with a negative interim scan result went on to receive 4 additional cycles of ABVD, but the 18% of patients with a positive PET scan result were treated with 6 cycles of escBEACOPP. Two-year PFS rates for the PET-negative and PETpositive groups were 82% and 67%, respectively, with a 2-year OS of 98% for all patients combined. Again, the intensification of therapy in the subset of PET-positive patients appears significantly better than historical controls. A randomized trial of standard chemotherapy versus intensified therapy for PET-positive patients in advanced HL will not be done because of small patient numbers as well as ethical concerns based on historical reports. In two completed studies for patients with advanced-stage HL, the German Hodgkin Study HD18 (NCT00515554) and LYSA AHL2011(NCT01358747), patients initiated treatment with 2 cycles of escBEACOPP. Those with negative interim PET results were deescalated to ABVD in the LYSA trial and were randomized to 2 versus 6 additional cycles of escBEACOPP in the HD18 trial. The hope and expectation is that over the coming years, we 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 results. Interim PET can also be used to safely deescalate therapy in patients with advanced-stage HL and negative PET results after 2 cycles of ABVD, specifically to omit bleomycin from cycles 3 through 6 of ABVD. In the RATHL trial, 1214 patients with advanced-stage HL received 2 cycles of ABVD followed by an interim PET.42 Patients with negative interim PET results were randomized to 4 cycles of ABVD versus 4 cycles of AVD (no bleomycin) in an effort to decrease pulmonary toxicity. Three-year PFS and OS were identical for the two arms (PFS, 85% versus 84%; OS, 97% versus 98%). The PETpositive group was intensified to BEACOPP with a 3-year PFS of 67%, very similar to other reports in this group. Based on the RATHL study, the standard of care for advanced-stage HL should be 2 cycles of ABVD followed by 4 cycles of AVD in those who are interim PET negative and escalation of chemotherapy in those that are PET positive. Additional approaches for the PET-positive group, including alternative salvage regimens and ASCT, are warranted. Results of the completed phase 3 study, ECHELON 1, comparing ABVD with AVD plus brentuximab vedotin (BV) in patients with previously untreated stage III to IV HL are eagerly awaited. The phase 1 study of AVD plus BV showed a CR rate of 96% and a 3 year FFS and OS of 96% and 100%, respectively.61,62 If AVD plus brentuximab proves superior to ABVD in this phase 3 trial, a new standard of care will be established for advanced-stage HL and may allow discontinuation of the escBEACOPP as first-line therapy.

Hodgkin Lymphoma  •  CHAPTER 102 1919

Therapy of Hodgkin Lymphoma in Pregnancy Given the young median age of patients with HL, occasionally women will be diagnosed during pregnancy. Current treatment recommendations are based on small series of patients with a variety of hematologic malignancies.63 Although guidelines continue to recommend consideration of termination for patients diagnosed during first trimester, many patients decline this option. The slow-growing nature of HL often makes it feasible to delay therapy until the second trimester for those diagnosed early in the course of their pregnancy or until after delivery in those diagnosed during the third trimester. As additional data emerge about the relative safety of standard chemotherapy for HL during the second and third trimesters of pregnancy, recommendations are often to proceed with standard ABVD chemotherapy in these patients.63,64 In a retrospective analysis of 40 patients diagnosed with HL during pregnancy, three patients in the first trimester elected termination, 13 patients deferred therapy (median, 34 weeks; gestation; range, 6–38), and 24 patients received therapy during pregnancy.64 The majority, 20 of 24, received ABVD or AVD chemotherapy, 13 starting in the second trimester and 7 in the third trimester. The 3-year PFS and OS were 85% and 97%, respectively. Median birth weights were similar among those electing treatment and those deferring treatment, and there were no fetal malformations among the 24 patients receiving treatment during pregnancy. Long-term follow-up of children with prenatal exposure to chemotherapy, including those exposed during the first trimester, have shown no significant differences in physical or cognitive development, cardiac abnormalities, or congenital malformations compared with the general population.65,66 However, prematurity was more common in these children and was associated with impaired cognitive development.65 Full-term delivery in all patients should be the goal.

Therapy of Hodgkin Lymphoma in Older Patients Approximately 15% to 20% of all HL occurs in patients older than 60 years of age.1 Trends in age-specific, 10-year relative survival of patients with HL between 1980 and 2004 show marked increases in all groups but particularly in patients aged 45 to 59 years (51.4% to 76.2%) and 60 years and older (21.6% to 44.9%).1 However, patients aged 60 years and older still have a much worse prognosis than younger patients. Inferior outcomes are attributable to higher IPS scores at diagnosis, as well as comorbid conditions that increase the morbidity and mortality associated with therapy.67 Patients older than 60 years of age are not candidates for aggressive regimens such as escBEACOPP and are often not eligible for salvage regimens incorporating ASCT. Proctor and coworkers reported a 14% toxic death rate during or immediately after completion of treatment in a series of 35 patients 60 years of age and older who received standard ABVD chemotherapy.68 Causes of death were sepsis in 4 patients and bleomycin pulmonary toxicity in 1 patient. Evens and coworkers reported a much higher incidence of bleomycin lung toxicity in patients older than 60 years of age, especially those receiving concurrent granulocyte colonystimulating factor (G-CSF).69 In this retrospective analysis of 92 HL patients aged 60 to 89 years, 32% of patients developed bleomycin lung toxicity, which was associated with a 25% mortality rate. Analysis of the large randomized trial of ABVD versus Stanford V showed the 5-year FFS for older adult patients was 48% and OS was 58%, significantly worse than for non–older adult patients (FFS, 74%; OS, 90%).70 Interestingly, the time to progression (TTP) was similar for younger and older patients, but deaths without progression were significantly higher in older patients. The GHSG (German Hodgkin Study Group) analyzed the outcomes of patients age 60 years or older treated with 4 cycles for ABVD for early-stage HL and noted substantial dose reductions, treatment delays, toxicity, and treatment-related mortality (5%) compared with younger patients.71 In a retrospective analysis of 147 patients aged 60 years and older treated with ABVD at three French centers, 31 (21%) had grade 3 or 4 pulmonary toxicity.72

The phase 3 RATHL trial showed that bleomycin can be safely eliminated for cycles 3 through 6 of ABVD in patients with a negative interim PET/CT after cycle 2.42 This approach may improve the tolerability of ABVD in patients older than 60 years of age. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) has also been proposed as an alternative to ABVD and in a small study of 29 older adult patients treated with CHOP-21, the CR rate was 93% with 2 treatment-related deaths.73 Three-year OS and PFS rates were 79% and 76%, respectively. Ongoing efforts to incorporate the very active and well-tolerated drug BV into first-line therapy may benefit older patients both in terms of improved efficacy and tolerability. Single-agent BV had a 92% overall response rate (ORR) and 73% CR rate in 27 patients 60 years of age or older with newly diagnosed HL.74 Unfortunately, the median remission duration was only 9.1 months, and 30% of patients experienced grade 3 peripheral neuropathy. Preliminary results of combinations of BV with dacarbazine or bendamustine in patients 60 years of age or older show response rates of 100%, which in early follow-up appear more durable than single-agent BV.75 However, despite dose reductions, the combination of BV and bendamustine was poorly tolerated in this study of older patients with excessive hematologic and neurologic toxicity. Older patients, regardless of age, should be treated with curative intent unless life-threatening comorbidities are present.

Therapy of Hodgkin Lymphoma in HIV In the era of highly active antiretroviral therapy (HAART), outcomes and therapy recommendations for HL in HIV-infected individuals mirror those of the non-HIV population. Montoto and coworkers reported on 224 consecutively treated patients with HL diagnosed between 1997 and 2010 at five university hospitals in London, including 93 HIV-positive patients and 131 HIV-negative patients.76 ABVD therapy was administered to 86% of the HIV-positive patients and 73% of the HIV-negative patients. Five-year disease-free survival rates were 85% and 87% for HIV-negative and HIV-positive patients, respectively. Similar favorable results were reported in 108 patients with HIV-associated HL treated with ABVD and IFRT if early-stage and 6 to 8 cycles of baseline BEACOPP in those with advanced-stage disease.77 Importantly, in both of these series, patients received concurrent HAART therapy and chemotherapy. Patients with HIV are not candidates for the escBEACOPP regimen.

THERAPY OF LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA In contrast to classical HL, there is no universal consensus regarding primary therapy of NLPHL. As previously discussed, it represents a unique pathobiological entity with a distinct clinical presentation and natural history. Historically, treatment of LP HL paralleled that of cHL, with most patients treated using extended- or regional-field RT, with or without chemotherapy. The majority of deaths in patients treated for NLPHL were related to late effects, primarily cardiovascular disease and second malignancies.78 Deaths from disease were rare. Based on these findings, efforts to develop distinct approaches for NLPHL have emerged. Small patient numbers and very favorable outcomes preclude randomized trials in this subtype of HL. Current approaches for early-stage disease include observation, most often in patients with a single site that has been resected; IFRT, most commonly neck, axillary, or inguinal RT as mediastinal involvement with NLPHL is rare; single-agent rituximab; or combinedmodality therapy. Chen and coworkers reported on 113 patients with early-stage NLPHL treated at the Dana Farber Cancer Institute (DFCI) between 1970 and 2005. Ten-year PFS rates were 85% (stage I) and 61% (stage II), with 10-year OS rates of 94% and 97%, respectively.78 Importantly, PFS and OS did not differ among patients who received involved-field, regional-field, or extended-field RT. Interestingly, 6 of 7 patients who received chemotherapy alone relapsed. During this

1920 Part III: Specific Malignancies

25-year period, only 3 of 113 patients died of HL, and 10 patients died of second malignancy (6), cardiac disease (2), or unrelated causes (2). In a report from the GHSG of 256 patients with stage IA NLPHL, outcomes were equivalent after CMT, extended-field RT, or IFRT, confirming the adequacy of IFRT for this presentation.79 In a study by the Children’s Oncology Group, 52 patients with stage IA NLPHL and a single node had complete resection followed by observation.80 Thirteen of the 52 patients relapsed at a median of 11.5 months with a 5-year EFS of 77.1% and 5-year OS of 100%. A total of 135 children with stage I to IIA received AV-PC chemotherapy followed by RT in 11 patients who did not achieve CR.80 Five-year EFS and OS were 88% and 100%, respectively, with more than 90% of patients avoiding RT. The risk benefit-to-ratio in children with early-stage NLPHL may favor chemotherapy alone, especially in patients with noncontiguous sites requiring larger radiation fields. The BCCA reported on 88 patients with limited-stage NLPHL treated between 1966 and 2009.81 Ten-year PFS rates were 65% for 32 patients treated with RT alone compared with 91% for the 56 patients treated with ABVD either alone (n = 14) or in combination with RT (n = 42). There were no deaths from NLPHL, and there were 3 deaths related to transformed diffuse large B-cell lymphoma (DLBCL). The current approach at the British Columbia Cancer Agency is 2 cycles of ABVD followed by a PET/CT. If interim PET results are negative, patients receive 2 additional cycles of ABVD and no RT, but if interim PET results are positive, they receive IFRT. Chemotherapy alone is a very reasonable approach for patients with stage IIA HL in which the IFRT may be larger, increasing the risk of second malignancies and other late complications. Single-agent rituximab has been used as primary therapy in earlystage disease with high response rates, but higher rates of early relapse than seen with RT or combined-modality therapy.82,83 A response rate of 100% was reported for 28 patients with stage I NLPHL with a 3-year PFS of 81%.83 Four doses of maintenance rituximab administered over 2 years resulted in a non-significant increase in PFS (67 months) compared with rituximab induction alone (50 months; P = .7)82 In patients with either advanced-stage or limited-stage disease requiring chemotherapy, the choice of regimen varies across centers. In contrast to results for early-stage patients, the BCCA reported less favorable results with ABVD in patients with advanced-stage NLPHL with a 63% 10-year TTP.84 Those with splenic involvement had a particularly poor outcome with a 10-year TTP of 48% compared with 71% in advanced-stage patients without splenic involvement (P = .048). In addition, 39% of patients with splenic involvement treated with ABVD had transformation to large-cell lymphoma compared with 9% of the spleen-negative group. A review of 37 NLPHL patients treated with chemotherapy on one of two clinical trials at DFCI showed 9 of 12 (75%) failures in patients treated with ABVD or EVA

(etoposide, vinblastine, doxorubicin) compared with 8 of 25 (32%) failures in patients treated with MOPP or MOPP/ABVD, suggesting perhaps an alkylator-based regimen may be superior in NLPHL.85 Fanale and coworkers reported a 100% response rate with R-CHOP (n = 15) or R-CHOP + IFRT (n = 5) and no relapses or transformations at a median follow-up of 42 months.86 Regardless of the choice of chemotherapy regimen, incorporating rituximab is justified based on the high single-agent response rates. Based on these small series, R-CHOP represents the standard approach for patients with NLPHL requiring systemic therapy. Long-term follow-up is essential in NLPHL because late relapses are common. Additionally, biopsy at time of recurrence is particularly important to detect transformation. Approximately 10% of patients with NLPHL have evidence of transformation to DLBCL.87,88 T-cell-rich large B-cell lymphoma is the most common subtype diagnosed at transformation.79,89

TREATMENT AND PROGNOSIS OF RELAPSED DISEASE Based on a randomized trial conducted in the 1990s, ASCT remains the preferred treatment for relapsed HL with cure rates of approximately 50%.90,91 There remains significant heterogeneity among treatment centers in the primary salvage regimen, the transplant preparative regimen, and the use of RT before or after ASCT. The relative rarity of this population likely precludes addressing these issues in a definitive way. However, strikingly similar results across studies and in retrospective comparisons at single centers in this population suggest that based on currently available treatments, these are not likely to represent major questions. More important than the precise procedural details of ASCT are how to improve selection of patients for ASCT with precise prognostic models and how to identify alternative novel options for the highest risk patients and those failing ASCT.

Prognostic Significance of Pretransplant Positron Emission Computed Tomography/ Computed Tomography 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 by PET/CT as the primary determinant of outcome.92–98 Table 102.4 summarizes the results of several small series showing ASCT outcomes based on pretransplant PET results. Nearly 80% of

Table 102.4  Selected Reports of Outcomes After Autologous Stem Cell Transplant Based on

Pretransplant Positron Emission Tomography Results

Study Moskowitz et al92 (2010) Smeltzer et al93 (2011) Mocikova et al94 (2011) Devillier et al95 (2012) Cocorocchio et al96 (2012) Gentzler98 (2014)

Patients With Pretransplant PET N (PET-, PET+)

EVENT-FREE SURVIVAL/ PROGRESSION-FREE SURVIVAL

OVERALL SURVIVAL P Value

PET-

PET+

153 (110, 42)

75% (5 yr)

31% (5 yr)

0.001

46 (23, 23) 76 (56, 20) 111 (85, 26) 40 (26, 14) 32 (13, 19)

82% (3 yr) 73% (2 yr) 79% (5 yr) 79% (5 yr) 85% (5 yr)

41% (3 yr) 36% (2 yr) 23% (5 yr) 43% (5 yr) 52% (5 yr)

0.02 0.01 < 0.001 < 0.01 0.09

NR, Not reported; PET, positron emission tomography.

PET-

PET+

P Value

91% (3 yr) 90% (2 yr) 90% (5 yr) 92% (5 yr) 100% (5 yr)

64% (3 yr) 61% (2 yr) 55% (5 yr) 43% (5 yr) 48% (5 yr)

0.08 0.009 0.001 <0.01 0.009

NR

Hodgkin Lymphoma  •  CHAPTER 102 1921

Table 102.5  Pretransplant Salvage Regimens Study

Regimen 148

Josting et al (2002) Moskowitz et al149 (2001) Santoro et al150 (2007) Bartlett et al103 (2007) Moccia et al151 (2017)

Patients (n)

Response Rate (%)

Complete Response Rate (%)

102 65 91 91 83

89 88 81 70 71

21 26 54 19 7

DHAP ICE IGEV GVD GDP

PFS/EFS Post-ASCT NR 68% (3.6-yr EFS) 53% (3-yr PFS) 52% 4-yr PFS) 57% (2-yr PFS)

aICE, Augmented ICE (ifosfamide and etoposide doubled); ASCT, autologous stem cell transplant; DHAP, cisplatin, cytarabine, dexamethasone; EFS, event-free survival; ICE, ifosfamide, carboplatin, etoposide; IGEV, ifosfamide, gemcitabine, vinorelbine; GDP, gemcitabine, dexamethasone, cisplatin; GVD, gemcitabine, vinorelbine, liposomal doxorubicin; PFS, progression-free survival.

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 to ASCT without delay. Overall and complete response rates for selected pretransplant salvage regimens are listed in Table 102.5. Most salvage regimens are designed to incorporate agents that are non–cross-resistant to ABVD such as ifosfamide, platinum, etoposide, gemcitabine, cytarabine, and steroids. No randomized trials have compared the effectiveness of conventional salvage regimens for relapsed HL. For those not achieving a PET CR with first-line salvage, an alternate regimen should be considered before ASCT. For those receiving initial salvage with a platinum-based regimen such as ICE (ifosfamide, carboplatin, etoposide), a gemcitabine-containing regimen such as GVD (gemcitabine, vinorelbine, and liposomal doxorubicin) represents a reasonable second-line salvage option (Fig. 102.6).99,103 Alternatively, single-agent BV is approved as second-line salvage with reported response rates of 76% in relapsed HL with a 34% CR rate.104,105 BV has been tested primarily in patients who have failed ASCT, by definition a more chemosensitive group than the group failing first-line salvage.

1.0 FDG-PET negative after GVD: 17 patients; 14 censored 0.8 FDG-PET negative after ICE: 59 patients; 48 censored EFS probability

patients with negative PET results pretransplant remain in remission 3 to 5 years after ASCT. Up to 40% of patients with positive pre-ASCT PET results will still experience a prolonged remission; therefore most centers proceed to ASCT in this subset of patients as long as there is no evidence of frank progression. Moskowitz and coworkers administered additional non–cross-resistant salvage therapy pre-ASCT in patients with a positive PET after first-line salvage.99 Patients achieving a PET CR after first-line salvage therapy and those with a PET 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. 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 that should consider alternatives to ASCT. Clinical factors at relapse that may complement prognostic information provided by the PET response to salvage therapy include time to relapse (≤12 mo versus >12 mo), advanced clinical stage, anemia, B symptoms, and bulky and extranodal disease.100,101 In a model including B symptoms, extranodal disease, and initial response less than 1 year, 5-yr EFS rates of 76% (zero or one factor), 35% (two factors), and 8% (three factors) were reported.102 Stratifying patients with relapsed HL into three groups based on risk factors of bulky and extranodal disease, patients with zero, one, or two risk factors achieved 6-year EFS of 65%, 47%, and 24%, respectively.101 Because of small patient numbers in each single-center series, it is not feasible to determine whether any of these clinical factors is independent of PET response pretransplant.

0.6 FDG-PET positive after GVD or ineligible: 21 patients; 6 censored

0.4

0.2

Log-rank test (P < .001) 0.0 0

12

24

36

48 60 Time (mo)

72

84

96

Figure 102.6  •  Event-free survival intent to treat by pre–autologous stem cell transplant response. FDG, Fluorine-18 fluorodeoxyglucose; GVD, gemcitabine, vinorelbine, and liposomal doxorubicin; ICE, ifosfamide, carboplatin, etoposide; PET, positron emission tomography. (Adapted from Moskowitz CH, Matasar MJ, Zelenetz AD, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non–cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7): 1665–1670.)

Several trials are exploring the use of BV as first-line salvage preASCT, either as a single agent or in combination. Two trials treated patients who failed one previous chemotherapy regimen with singleagent BV and assessed response by PET/CT after 2 cycles.106,107 Patients achieving CR proceeded to ASCT (27%–35% of patients) and those with residual disease received additional salvage therapy, most commonly ICE, before transplant. With this sequential approach, approximately one-third of patients were able to avoid aggressive salvage pre-ASCT, and approximately 75% achieved PET-negative CR with either BV or conventional chemotherapy. Preliminary results of phase 1 and 2 trials investigating concurrent BV with standard salvage regimens such as ICE, ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), or bendamustine also appear promising with acceptable

Progression-free survival by investigator assessment (%)

1922 Part III: Specific Malignancies

100 90 80 70 60 50 40 30 20 10 0

HR, 0.50 (95% CI, 0.35−0.70) 0

4

8

12

16

20

24 28 32 Time (months)

36

40

44

48

52

Figure 102.7  •  Progression-free survival. CI, Confidence interval; HR, hazard ratio. (Adapted from Moskowitz CH, Nademanee A, Masszi T, et al.

Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853–1862.)

toxicity profiles and high CR rates pre-ASCT.108–110 Approaches incorporating BV into first-line salvage appear promising but are still investigational.

Posttransplant Maintenance Therapy In 2015, the Food and Drug Administration approved the use of BV as maintenance therapy after ASCT for relapsed HL based on the results of an international phase 3 trial.111 A total of 329 patients with high risk HL were enrolled on this placebo-controlled, double-blind phase 3 trial and randomized to receive 16 cycles of BV versus placebo starting 4–6 weeks after ASCT. Eligible patients had to have at least one high-risk feature, defined as failure to achieve complete remission with initial chemotherapy, disease progression within 1 year of completion of initial therapy, or extranodal involvement at time of disease progression. After a median follow-up period of 30 months, the estimated 2-year PFS was 65% in the BV group versus 45% in the placebo group (HR, 0.55) (Fig. 102.7). Neuropathy and neutropenia were more common in the BV-treated group, and one-third of patients discontinued treatment because of toxicity. Patients were unblinded and crossover was allowed at progression. Importantly, there was no difference in the OS, which raises the possibility that similar outcomes could be achieved if patients were treated with BV at progression instead of as maintenance.

Role of Allogeneic Stem Cell Transplantation Allogeneic SCT (allo-SCT) has the theoretical advantages of a tumorfree stem cell source, additional antitumor activity, and a decrease in secondary MDS and acute leukemia, but high treatment-related mortality rates usually preclude consideration of this approach at the time of first progression. However, reduced intensity conditioning or nonmyeloablative allogeneic transplant is an option for relapse following ASCT. Outcomes with allo-SCT have improved likely because of improvements in supportive care, as well as more effective pretransplant salvage. In a systematic review and meta-analysis of 42 reports (1850 patients) of allo-SCT for relapsed HL, the pooled estimates for 1-, 2-, and 3-year relapse-free survival were 50%, 37%, and 31% respectively, with corresponding numbers for OS of 68%, 58%, and 50% and for nonrelapse mortality (NRM) of 19%, 19%, and 19%.112 Importantly, when the series were analyzed independently for studies with accrual initiation in 2000 or later versus before 2000, both relapse-free survival and OS improved by 15% to 20%, and NRM decreased by 5% to 10% in the later era. Outcomes for patients with chemosensitive disease pre-alloSCT were superior to those with chemorefractory disease. Recent reports of encouraging results of haploidentical transplantation with posttransplant cyclophosphamide

for relapsed HL may increase the pool of potential candidates for this approach. In a multicenter study of 62 patients undergoing haploidentical transplant for relapsed HL, the 3-year OS, PFS, and NRM were 63%, 59%, and 20% respectively.113 Responses after donor lymphocyte infusions provide evidence of graft versus HL effect.114,115 The role of allo-SCT may change as drugs with novel mechanisms of action continue to be developed.

New Drugs As discussed extensively earlier, BV (SGN-35), an antibody–drug conjugate composed of an anti-CD30 antibody (cAC10) conjugated to monomethylauristatin E (MMAE), a potent antimicrotubule agent was approved by the FDA in 2011 for patients with relapsed or refractory HL after at least two prior lines of treatment and in 2015 as maintenance after ASCT and is now under investigation in earlier lines of therapy.116 In a pivotal phase 2 trial, single-agent BV 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.104 The median PFS was 5.6 months, and in patients who achieved a CR, the median duration of response was 20.5 months. Common BV toxicities include peripheral sensory neuropathy (42%), neutropenia (19%), and diarrhea (18%). No febrile neutropenia or treatment-related deaths occurred in the phase 2 study. Peripheral sensory neuropathy is reversible in most patients. BV is contraindicated in combination with bleomycin given the increased incidence of severe and fatal pulmonary toxicity seen in a phase 1 study of BV plus ABVD chemotherapy.61 Retreatment with brentuximab in patients with relapsed HL who previously responded to BV resulted in a 60% response rate in 15 patients, including 3 complete remissions.117 As with many other cancers, the PD-1 inhibitors have shown remarkable activity in relapsed and refractory HL with nivolumab approved for patients who have failed ASCT and pembrolizumab approved for refractory patients or patients relapsed after ≥3 lines of treatment.118–120 Phase 2 studies of these agents showed an ORR of approximately 65% with 9% to 16% CR rate at early follow-up.119,120 These agents are under investigation in earlier lines of therapy, specifically as first-line salvage in combination with BV. The label for nivolumab includes a warning regarding the increased risk of fatal graft-versus-host disease in patients undergoing allogeneic transplant after treatment with nivolumab. Other novel agents with activity in relapsed or refractory HL include histone deacetylase (HDAC) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, immunomodulatory agents, and the bialkylator bendamustine. Panobinostat, a pan-HDAC inhibitor, showed modest activity in a phase 2 study in relapsed and refractory

Hodgkin Lymphoma  •  CHAPTER 102 1923

1965−1976

Cumulative incidence (%)

HL after ASCT with an overall response rate of 27% (4% CR) and a median duration of response of 6.9 months.121 A phase 2 trial of the mTOR inhibitor everolimus reported an ORR of 37% (5% CR) in 38 relapsed HL patients.122 The median duration of response was 7.1 months, and median PFS was 6.2 months. Lenalidomide, an immunomodulatory agent, showed modest activity in 38 patients with relapsed or refractory HL with an ORR was 18% (3% CR), median duration of response was 6 months, and median PFS was 4 months.123 A retrospective analysis of 41 patients treated with bendamustine reported a response rate of 58% (31% CR).124 The median duration of response was 9 months, and median PFS exceeded 11 months. A prospective phase 2 study of bendamustine enrolled 36 relapsed or refractory HL patients and reported an ORR of 53% (33% CR).125 The mean response duration was 5.7 months, but PFS and OS have not been reported. Combinations of new agents with standard therapies are under investigation.

50

90

40

80

30

70

20

60

1989−2000

10

50

0

40

0 5 10 15 20 25 30 35 40 45

30 20 10 0

LATE COMPLICATIONS OF THERAPY FOR HODGKIN LYMPHOMA Balancing efficacy with long-term toxicity has long been a goal of HL therapy. This has proven to be an extraordinary challenge, primarily related to the significant delay of more than 10 years, and in many cases, 30 years, between HL therapy and its associated complications. Evaluating alterations in therapy requires decades of follow-up to determine if new approaches have indeed accomplished the goal of decreased long-term toxicity. Dissecting the late effects of chemotherapy versus radiation when a large percentage of patients receive both modalities presents an additional hurdle. Finally, currently undefined potential host factors in patients with HL, such as subtle immune deficiencies or genetic susceptibilities to cancer, continue to represent potential explanations for at least a portion of the second malignancies. In addition to advances in therapy, research continues on methods to enhance cardiovascular and malignancy screening in HL survivors.126

100

1977−1988

0

5

10

15

20

25

30

35

40

45

Follow-up (yr)

Figure 102.8  •  Cumulative incidence of subsequent malignant neoplasm,

according to treatment period, with death as a competing risk. Solid lines represent the observed incidence, and dashed lines the expected incidence in the general population. The insets show the same data on enlarged y-axes. (Adapted from Schaapveld M, Aleman BMP, van Eggermond AM, et al. Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med. 2015;373(26):2499–2511.)

Table 102.6  Cumulative Breast Cancer Risk at 20

and 40 Years After Radiotherapy

CUMULATIVE BREAST CANCER RISK AFTER RT (%)

Second Cancers

Age at RT (Yr)

Unfortunately, despite the reduction in radiation field size and dose and the decreased use of alkylating agents as first-line therapy, recent reports continue to describe an overall risk of second cancer in HL survivors that is 4.6 times as high as the risk of cancer in the general population.39,127 In this large registry study in the Netherlands, the cumulative incidence of second solid cancers did not differ according to study period (1965–1976, 1977–1988, 1989–2000) (Fig. 102.8).127 Encouragingly, the risk of breast cancer was lower among patients not receiving axillary radiation. 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 standardized incidence ratio (SIR) of 47 for those treated at age 14 (Table 102.6).128 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 of lung cancer is also substantially increased after both RT and chemotherapy for HL and occurs most commonly in smokers but not exclusively.129 In contrast to breast cancer, an increased risk of lung cancer is seen even in the first 5 years after treatment, especially in those treated with alkylating agents, potentially suggesting a different mechanism for cancer induction.130 Smoking increases the risk of lung cancer more than 20-fold in HL survivors and appears multiplicative, not additive, in combination with RT.130 In addition, the risk of lung cancer in HL survivors was 3.3-fold higher in patients with a family history of lung cancer, suggesting a more than additive interaction between family history and treatment for HL.131 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

0–9 10–14 15–19 20–24 25–29 30–35

20 Yr

40 Yr

0 6.80 6.40 3.50 7.40 9.80

0 34.50 36.10 29.20 17.40 27.50

8.80 4.30

22.80 23.20

Mantle RT Dose (Gy) 1–34 36–39

RT, Radiotherapy. Adapted from Swerdlow AJ, Cooke R, Bates A, et al. Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in England and Wales: a national cohort study. J Clin Oncol. 2012;30(22): 2745–2752.

breast cancer.132 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 SIR of 22.9 for second cancers with a cumulative incidence of 17% at 20 years.133 The incidence of lung cancer also appears to follow a dose-response relationship.130 The GHSG HD10 and HD11 trials, which compared limited chemotherapy combined with 20- or 30-Gy IFRT in early-stage HL, reported a 4% to 8% incidence of second malignancy at a median follow-up of 10 years with no difference in the incidence of second malignancies or deaths from second cancers in those receiving 20 versus 30 Gy.35 Genome-wide association studies in HL survivors have investigated variants that may be associated with RT-induced second cancers, and future tests may be available for HL patients to determine their genetic susceptibility

1924 Part III: Specific Malignancies

to RT-induced cancers, possibly influencing the decision to include RT in treatment for 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 compared with sporadic breast cancer.134 HL survivors had a breast cancer–specific mortality rate similar to matched control participants with sporadic breast cancer but a marked increased risk of 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.134 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.135

Cardiovascular and Cerebrovascular Complications Compared with population-based reference rates, HL survivors face an increased risk of myocardial infarction (MI), congestive heart failure (CHF), and valvular disorders, with a 40-year cumulative incidence of 50% with the highest relative risks seen in patients treated before age 25 years but increased risk noted for patients in every age group.136 Twenty-five year cumulative risks of CHF after mediastinal RT of 0 to 15 Gy, 16 to 20 Gy, and 21 Gy or greater were 4.4%, 6.2%, and 13.3%, respectively, in patients treated without anthracyclines and 11.2%, 15.9%, and 32.9%, respectively, in patients treated with anthracyclines.137 Swerdlow and coworkers found a standardized mortality ratio (SMR) of 2.5 for fatal MI in HL survivors.138 Risks were independently increased for patients treated with RT, anthracyclines, or vincristine. Risk was particularly high for patients receiving ABVD chemotherapy (SMR, 9.5), including those who received ABVD but no mediastinal RT (SMR, 7.8).138 The SIR 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.139 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 below for aggressive treatment of coexisting 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 ABVD, is considered nonsterilizing. 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. Conflicting reports regarding the use of oral contraceptives and gonadotropin-releasing hormones to protect the ovarian follicle pool during treatment with alkylators have been published.54 Before initiating therapy for HL, all male patients should be offered cryopreservation and banking of sperm because this process is noninvasive and effective. Consultation 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) or ASCT should be referred. After any treatment for 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 US Preventative Services Task Force.140,141 Evaluations of second malignancy risk in HL survivors should also take into account family history, details of the treatment, environmental factors such as smoking, and comorbid 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 and 30 years, annual breast magnetic resonance imaging should be done in conjunction with annual mammography.142,143 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.141 Screening for cardiovascular disease should include a lipid panel every 3 years with statin therapy recommended for those with a low-density lipoprotein cholesterol over 100 mg/dL, a fasting glucose 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.34,144–146 Carotid Doppler is unlikely to be a useful screening tool for cerebrovascular disease based on the very low incidence of significant stenosis in HL survivors having a cerebrovascular accident.139 Patient education, counseling, and surveillance for late complications are essential aspects of lifelong follow-up care for HL survivors.

CONTROVERSIES, PROBLEMS, AND CHALLENGES The two primary controversies in the treatment of HL remain the use of chemotherapy alone versus combined-modality therapy in early-stage HL and the use of ABVD versus escBEACOPP in advancedstage disease. Both of these debates hinge on the finding that an inferior PFS does not necessarily equate to an inferior OS. Although chemotherapy alone in early-stage disease and ABVD in advanced-stage disease result in higher rates of relapse, the acute toxicities and late effects challenge us to look at OS as the primary endpoint. The need to wait more than 20 years to see the potential life-threatening late effects of therapy requires patience and continued long-term follow-up of all patients with HL. The recent development of novel active agents for relapsed HL, such as BV and PD-1 inhibitors, provides the opportunity to incorporate new drugs into first-line regimens in an effort to improve outcomes further without the attendant toxicities associated with RT and dose intensive approaches. Additional challenges include how best to select patients both for more intensive or novel first-line approaches, as well as those who would benefit from less therapy. Although interim PET/CT scans have proved useful, the specificity of a positive interim scan result is inconsistent, and better methods of interpretation are needed. The approach to relapsed HL remains variable with regards to the pretransplant salvage regimen and the role of reduced intensity conditioning allogeneic stem cell transplant at first or subsequent relapse. Although outcomes are quite favorable for most patients with HL, we should not give up our “pursuit of perfection” in this disease.147

CONCLUSIONS Despite the relatively low incidence of HL, the young age of many patients with the disease increases the societal impact of incremental improvements in treatment. We need to continue efforts to minimize the long-term sequelae of therapy by incorporating interim and endof-treatment PET/CT scans into our treatment decisions. Additional biological markers that reliably predict outcome are needed. The highest priority is determining how to integrate new effective treatments such as BV and PD-1 inhibitors into earlier lines of therapy without increasing the toxicity of current regimens. The complete reference list is available online at ExpertConsult.com.

Hodgkin Lymphoma  •  CHAPTER 102 1925

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Hodgkin Lymphoma  •  CHAPTER 102 1925.e1 1925.e1

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