The Washington Manual of Oncology, 3 Ed.

Hodgkin’s Lymphoma

Nancy L. Bartlett • Nina D. Wagner-Johnston

 I. HODGKIN’S LYMPHOMA

1. Presentation
2. Subjective. Classical Hodgkin’s lymphoma (HL) usually presents as painless lymphadenopathy in the cervical and/or supraclavicular regions. Isolated subdiaphragmatic lymphadenopathy or organ involvement is rare. Although staging studies reveal mediastinal adenopathy in more than 85% of patients, symptoms of cough, chest pain, dyspnea, and superior vena cava (SVC) syndrome are uncommon, even in patients with bulky mediastinal disease. Systemic symptoms or “B” symptoms, including fevers (temperature greater than 38°C), drenching night sweats, or weight loss (more than 10% of baseline body weight in the preceding 6 months) occur in 30% to 40% of patients with stage III or IV disease, but in fewer than 10% of patients with stage I or II disease. In most series, the presence of B symptoms portends a worse prognosis. Generalized, severe pruritus occurs in approximately 25% of patients with HL, often precedes the diagnosis by months, can be a presenting symptom of both early and advanced-stage disease, and has no known prognostic significance. Alcohol-induced pain in involved lymph nodes is a rare symptom of HL (less than 1%). B symptoms and pruritus usually subside within a few days of initiating therapy. When HL presents in older patients or patients with human immunodeficiency virus (HIV), B symptoms and intra-abdominal and extranodal involvement including lung, bone marrow, liver, or bone are more common. HL should always be considered in the differential diagnosis of fever of unknown origin in an older patient, even without evidence of adenopathy.

 Nodular lymphocyte-predominant Hodgkin’s lymphoma (LPHL), which represents less than 5% of cases of HL in the United States and Europe, is often first seen as a solitary cervical, axillary, or inguinal lymph node. In LPHL, the mediastinum is generally spared, and in contrast to the contiguous pattern of lymph node involvement in classic HL, there is no consistent pattern of spread.

2. Objective. Although computed tomography (CT) scans and positron emission tomography (PET) scans have replaced the physical examination in staging, thorough examination of all lymph node–bearing areas in patients with HL remains pertinent. Occasionally, small supraclavicular and infraclavicular nodes can be missed on neck and chest CT scans. In addition, chest CT scans do not always include the entire axillae, especially in larger patients. Physiologic uptake in the sternocleidomastoid muscles on PET scan may decrease the sensitivity of this test in the cervical and supraclavicular regions. Identification of all involved nodal areas is especially important in early-stage patients who may receive limited chemotherapy and involved field radiotherapy (IFRT).
3. Workup and staging. HL is nearly always diagnosed by an excisional lymph node biopsy, although rarely, biopsy of an extranodal site may be the source of diagnostic tissue. Diagnosis requires the presence of Hodgkin’s and Reed–Sternberg cells (HRS) within an appropriate cellular background of inflammatory cells. Despite improved diagnostic techniques, excisional biopsies are preferred over core needle biopsies to adequately assess the architecture and the presence of the rare HRS cells. The classification system proposed by the World Health Organization (WHO) classifies HL as either “classical” HL or nodular LPHL. This distinction is essential because LPHL and classical HL have different natural histories, prognoses, and treatments. Immunohistochemical studies accurately distinguish classical HL from LPHL. In classical HL, the large atypical cells generally express CD15 and CD30, whereas other T-cell and B-cell–associated antigens are usually negative. In contrast, the tumor cells of LPHL are CD20⁺ (a pan–B-cell antigen), CD45⁺ (leukocyte common antigen), CD15⁻, and variably reactive for CD30, an immunophenotype often seen in B-cell NHL. Flow cytometry is not a useful diagnostic test in HL.

 Pathologists continue to describe four patterns of classical HL, including nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depletion. Nodular sclerosis Hodgkin’s lymphoma (NSHL) is the most common type (60% to 80%), accounting for most cases of HL in young adults and those with mediastinal involvement. With current therapies, these subtypes have little prognostic significance.

 Additional workup after a diagnostic lymph node biopsy includes a history and physical examination, laboratory evaluations, radiographic studies, and in some cases, a bone marrow biopsy. Necessary laboratory tests include a complete blood count (CBC), alkaline phosphatase, calcium, albumin, and erythrocyte sedimentation rate. A significant minority of patients have mild leukocytosis, neutrophilia, lymphopenia, and rarely eosinophilia. HIV testing is recommended. Elevated alkaline phosphatase is common and does not necessarily signify liver or bone involvement. Anemia and decreased albumin are usually seen only in patients with B symptoms and stage III or IV disease.

 The Ann Arbor staging system for HL is detailed in Table 25-1. The designation E applies to extranodal involvement, which is limited in extent and contiguous with lymph node disease. Since the inception of the classification system in 1971, subtle modifications have been suggested but never universally adopted. Proper staging requires a whole body PET/CT scan. The mediastinal mass ratio (MMR), defined as the ratio of the maximal transverse diameter of the mediastinal mass to the maximal transverse intrathoracic diameter, is an important prognostic factor and should be calculated in all patients with significant mediastinal adenopathy. An MMR greater than 0.33 by chest radiograph (CXR) or 0.35 by CT portends a worse prognosis and influences treatment recommendations. Traditionally, bilateral bone marrow biopsies were recommended in patients with B symptoms, known stage III or IV disease, or a subdiaphragmatic presentation of stage I or II disease. However, in the age of PET/CT, results of the bone marrow biopsy are unlikely to change the prognosis or treatment strategy and can likely be eliminated as part of the routine workup.

1. Therapy and prognosis. The treatment of HL has been a true success story, with approximately 80% of all patients having durable remissions. Current efforts are aimed at minimizing therapy in an effort to avoid both short- and long-term complications. Tailoring therapy based on results of an interim PET/CT scan following one to three cycles of chemotherapy may offer the best approach, yet mature data from randomized trials are not yet available.
2. Stage I/II classical Hodgkin’s lymphoma: low risk. Early-stage HL is usually considered “favorable” or low risk if there are no B symptoms and no sites of bulky disease, with bulk commonly defined as an MMR greater than 0.33 or a nodal mass greater than 10 cm. With current treatment strategies, nearly 90% of patients with early favorable HL are cured, yet debate continues regarding the best approach to treatment secondary to concerns of late toxicities. Short course chemotherapy, such as with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), followed by radiotherapy has been the standard of care for early stage HL adults for the last two decades. In the HD10 trial for early favorable HL, the German Hodgkin Study Group demonstrated no difference in 5-year freedom from treatment failure (FFTF) with two cycles of ABVD followed by 20 Gy IFRT compared with four cycles of ABVD and 30 Gy IFRT (N Engl J Med 2010;363:640). Intuitively, less treatment led to less acute toxicity. Longer follow-up is required to determine if the lower radiation dose decreases the known late sequelae of radiation, including second malignancies, cardiovascular disease, pulmonary fibrosis, and hypothyroidism. Of concern, at a median follow-up of 7.5 years, 4.6% of patients in the HD10 trial developed second malignancies, and at early follow-up, there was no difference in the incidence between the 20 and 30 Gy arms. Importantly, eligible patients included only those with disease limited to no more than two sites, no extranodal or bulky disease, and ESR <50 if no B symptoms and <30 in the presence of B symptoms. Involved node radiotherapy (INRT) has gradually become accepted as an alternative for IFRT; however, because mediastinal nodes are involved in the majority of patients with HL, most patients undergoing radiation will continue to have at least modest exposure to the heart, lungs, and breasts regardless of efforts to minimize treatment fields.

 Omission of radiation altogether may be feasible in carefully selected patients. Chemotherapy alone is particularly appealing in women aged 15 to 30 years, a subgroup particularly susceptible to second breast cancers after mediastinal and axillary radiation; smokers, due to a marked increase risk of lung cancer after mediastinal RT; and patients with a strong family history of cardiovascular disease. Long-term follow-up of a randomized study of ABVD alone versus radiation-based therapy in patients with limited stage HL demonstrated a survival advantage in the chemotherapy alone arm (94% vs. 87%, p = 0.04), despite inferior progression-free survival (PFS) (N Engl J Med 2012;366:399). While this study utilized an outmoded field and dose of radiation, the finding that chemotherapy was sufficient alone as curative therapy for the majority of patients with favorable disease is still applicable.

 A negative early interim PET/CT scan is a strong predictor of prolonged PFS (Blood 2006;107:52). The United Kingdom RAPID trial treated clinical stage I/IIA non-bulky HL patients with three cycles of ABVD and randomized PET negative patients to IFRT versus no further treatment (Blood 2012;120: abstract. 547). Nearly 75% of patients had a negative PET/CT scan following three cycles of ABVD. The 3-year PFS and OS rates were 93.8% and 97%, respectively, in the 209 PET-negative patients randomized to IFRT, compared with 90.7% and 99.5%, respectively, in the 211 PET-negative patients randomized to no further treatment. These very encouraging results support the use of ABVD alone in patients who achieve an early negative interim PET/CT.

2. Stage I/II classical Hodgkin’s lymphoma: high risk. The standard treatment for patients with less favorable limited-stage disease, including those with bulky disease, is combined modality therapy. At least 80% of patients are cured with this approach. Standard therapy is four to six cycles of ABVD followed by IFRT. A large cooperative group trial, E2496, for patients with bulky stage I/II HL and good prognosis stage III/IV HL comparing ABVD with the Stanford V regimen plus 36 Gy modified IFRT enrolled 268 patients with stage I/II bulky disease (J Clin Oncol 2013;31:684). In the bulky patients, the 5-year PFS and OS rates were 82% and 94%, respectively, with no difference between treatment arms. Randomized trials in early stage bulky HL specifically addressing the role of radiotherapy are not available. In British Columbia, the decision to use CMT is based on the result of an end-of-treatment PET/CT following completion of ABVD. In a retrospective analysis, patients with initial bulky disease and a negative PET after chemotherapy had a 3-year time to progression of 86% without the use of consolidative RT (J Clin Oncol 2011;29: 8034). Phase II studies evaluating outcomes of chemotherapy alone in patients with a negative interim PET are ongoing. Outside the context of a clinical trial, combined modality therapy, including ABVD × 4 to 6 cycles plus 30 Gy IFRT/INRT, remains the standard of care, although for those with a negative interim and end-of-treatment PET, chemotherapy alone is likely adequate in the majority of patients.
3. Stage III/IV classical HL. Approximately 60% to 70% of patients with advanced-stage HL can be cured with six cycles of ABVD chemotherapy, the current standard of care. The International Prognostic Factors Project on advanced HL identified seven independent prognostic factors in 1,618 patients with advanced-stage HL (N Engl J Med 1998;329:1506). These include serum albumin less than 4 g/dL, hemoglobin less than 10.5 g/dL, male sex, age 45 years or older, stage IV disease, leukocytosis (white blood cells [WBC] greater than 15,000/mm³), and lymphocytopenia (lymphocyte count less than 600/mm³ and/or lymphocyte count less than 8% of the WBC). The International Prognostic Score (IPS) showed that patients at the lowest risk with zero to two high risk features had a 67% to 84% freedom from progression (FFP) at 5 years, whereas those at highest risk with four to seven adverse risk factors had a 42% to 51% FFP. A more recent study evaluating prognosis according to the IPS score among 740 patients treated between 1980 and 2010 showed more favorable outcomes compared with the initial publication, with 5-year PFS rates of 81% for lower risk patients (IPS 0–3) and 65% for high risk patients (IPS 4–7) (J Clin Oncol 2012;30:3383). Justifying changes to the initial management based on the IPS score are challenging with these narrower range of outcomes. Early interim PET/CT scans may overcome these challenges and allow us to successfully tailor therapy. In the frequently described multivariate analysis by Gallamini et al., PET results following two cycles of ABVD were prognostically superior to the IPS factors (J Clin Oncol 2007;25:3746).

 The German Hodgkin’s Study Group continues to advocate the more intense regimen of dose-escalated (esc)BEACOPP (bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine, procarbazine, and prednisone) for patients with advanced-stage HL (Table 25-2). Ten-year follow-up of the randomized trial comparing COPP/ABVD with escBEACOPP chemotherapy demonstrated FFTF of 64% versus 82% and OS of 75% versus 86%, respectively (J Clin Oncol 2009;27:4548–54). Despite these encouraging results, many oncologists are reluctant to recommend escBEACOPP because of toxicity concerns. escBEACOPP results in azoospermia and infertility in the majority of male patients and in premature menopause in the majority of female patients over the age of 30 years. Eight cycles of escBEACOPP were associated with a 20% incidence of grade 3–4 infections and a 3% risk of secondary acute leukemia. However, a randomized trial of six versus eight cycles showed a more favorable toxicity profile with fewer cycles, with a lower incidence of leukemia and myelodysplastic syndrome (0.3% vs. 2.8%) (Lancet 2012;379:1791). These added toxicities may be acceptable in the highest risk patients if improved overall survival (OS) rates can be confirmed. Ideally, we will be able to tailor therapy more effectively in the future by escalating to more toxic therapy in the small subset of patients with early positive interim PET.

4. LPHL. Nodular LPHL is characterized by its indolent nature and favorable prognosis. Nearly 80% of patients present with early stage disease. Ten-year PFS rates of 85% (stage I) and 61% (stage II) and OS rates of 94% (stage I) and 97% (stage II) were described in a single-institution study of over 100 patients treated between 1970 and 2005 (J Clin Oncol 2010;28:136). Deaths due to disease are rare with the majority of deaths being potentially treatment-related, primarily cardiac disease and second malignancies. Of note, patients with LPHL are at risk of transformation to diffuse large B-cell lymphoma, especially in the setting of intra-abdominal disease. Most physicians currently recommend either observation following resection or IFRT alone for treatment of early-stage LPHL. Because most patients are first seen with stage I disease in the neck, axilla, or groin, exposure of normal tissues is relatively limited with IFRT. Treatment for the rare patient with stage III to IV disease continues to be chemotherapy usually in combination with rituximab (Blood2013;122:4288). While some advocate the use of standard HL regimens such as ABVD, outstanding results have been reported with R-CHOP chemotherapy.
5. Recurrent Hodgkin’s lymphoma. All patients younger than 70 years who relapse after chemotherapy or combined modality therapy should be considered for autologous hematopoietic cell transplant (HCT). Initially patients should receive one of several effective salvage regimens for two to four cycles to reduce tumor burden. Non–cross-resistant regimens such as ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) and ICE (ifosfamide, carboplatin, etoposide) are associated with response rates of 73% to 88% in relapsed HL. Treatment with GND (gemcitabine, vinorelbine, and liposomal doxorubicin) is a reasonable salvage regimen for non-transplant candidates or those not responding to platinum-based salvage regimens.

 High dose chemotherapy with HCT is associated with PFS rates of 40% to 50%. Salvage therapy is most likely to be successful in patients whose initial remission is longer than 12 months, whose relapse is confined to limited sites including no bone marrow or pulmonary involvement at relapse, and who are without constitutional symptoms. The best approach for patients with favorable early-stage disease, treated with chemotherapy alone, who relapse in initial sites of disease must still be determined. Radiation or standard-dose salvage chemotherapy followed by radiation may be adequate in patients with a first remission lasting more than 12 months and relapse limited to the initial site(s) of disease with HCT reserved for second relapse.

 Brentuximab vedotin, an anti-CD30 antibody conjugated to a potent microtubule inhibitor, monomethyl auristatin E (MMAE), is approved for patients with relapsed or refractory HL following at least two prior lines of treatment. In a pivotal phase II trial, brentuximab vedotin had an overall response rate of 75%, with a median PFS of 5.6 months (J Clin Oncol 2012;30:2183). Among the 34% of patients who achieved a complete response, the median duration of response was 20.5 months. Retreatment with brentuximab vedotin in previously responding patients is an effective option, with a recent report describing a 60% ORR with 30% CR (J Hematol Oncol 2014;7:1).

 Patients who relapse after treatment with brentuximab vedotin are candidates for investigational drugs. In a recent cohort expansion phase I study of 23 patients with relapsed HL, treatment with a PD-1 blocking antibody, nivolumab, was associated with an ORR of 87% and a PFS of 86% at 24 weeks. 78% of patients had relapsed following treatment with brentuximab vedotin and 78% had relapsed following HCT (N Engl JMed 2014; Epub ahead of print). A phase II study of bendamustine reported an ORR of 53% with a median PFS of 5.2 months (J Clin Oncol 2013;31:456). Modest activity has been described with novel agents, including panobinostat, lenalidomide, and everolimus. Palliation for months or years is often possible with sequential use of single-agent chemotherapy. Vinblastine, chlorambucil, oral etoposide, CNNU, vinorelbine, and gemcitabine have all shown activity in this setting.

1. Follow-up. Seventy percent of all relapses occur in the first 2 years after therapy, and fewer than 10% occur after 5 years. History and physical examination alone detect 70% to 80% of all recurrences, with at least half of these identified at appointments arranged by the patient for evaluation of symptoms, not at routine follow-up. A common practice is to perform a history and physical examination every 3 to 4 months for the first 2 years, and then every 4 to 6 months for the following 3 years. A routine annual CXR for the first 2 years detects most of the remainder of the asymptomatic recurrences. Additional routine laboratory tests and radiographs rarely detect asymptomatic recurrences. An annual thyroid-stimulating hormone (TSH) test should be performed in all patients treated with mediastinal or neck radiation. CT scans should probably not be performed more often than annually for the first 2 years after therapy, if at all, and only for evaluation of symptoms thereafter. After 5 years, a history and physical examination should be obtained annually to screen for late complications; follow-up with either an oncologist or a primary care physician is appropriate at this time.

 Greater emphasis should be placed on patient education, rather than on routine follow-up testing. Patients should be familiar with symptoms and patterns of relapse as well as signs and symptoms of late complications, including thyroid disease, second cancers, and cardiac disease. Education about the need to minimize sun exposure, avoid smoking, and reduce cardiovascular risk factors is essential. Women who received mediastinal or axillary radiation should be encouraged to do breast self-examinations, and annual mammograms should be initiated 7 to 10 years after completion of treatment. An annual breast MRI should be performed in conjunction with an annual mammogram in female patients treated with mediastinal or axillary radiation between the ages of 10 and 30. An annual low dose spiral chest CT should be considered in current or former smokers starting 5 years after treatment with alkylators and 10 years after treatment with supradiaphragmatic radiation. A cardiac stress test should be considered approximately every 5 to 10 years after mediastinal RT to evaluate for coronary artery disease.

1. Background
2. Epidemiology and risk factors. Approximately 9,000 cases of HL are diagnosed annually in the United States. HL has a bimodal age distribution in developed countries, with the first peak occurring in the third decade of life and the second peak occurring after the age of 50 years. Men have a slightly higher incidence than women. There is an association between HL and factors that decrease exposure to infectious agents at an early age, including advanced maternal education, early birth order, decreased number of siblings, and living in a single-family residence. A history of infectious mononucleosis increases the risk of HL two- to threefold and suggests Epstein–Barr virus (EBV) as an etiologic agent. Although 30% to 50% of patients with HL have detectable EBV DNA in the HRS cells, direct evidence of a causative role is lacking. There is a slightly increased risk of HL in patients infected with HIV, but not in other conditions associated with chronic immunosuppression. An increased incidence among first-degree relatives, a significant concordance rate among identical, but not fraternal twins, and linkage with certain human leukocyte antigen (HLA) types suggest a genetic predisposition for HL.
3. Molecular biology. The amplification and analysis of genes of single HRS cells has provided overwhelming evidence that at least 95% of HL cases represent monoclonal B-cell disorders. Clonal immunoglobulin gene rearrangements are present in the HRS cells of both classical HL and LPHL.
4. Genetics. Cytogenetic analysis in lymph nodes involved by HL is limited because of the low number of obtainable mitoses from lymph node suspensions and the inability to attribute abnormalities to the malignant cells. A specific chromosomal marker of HL has not been identified, but a variety of numeric and structural abnormalities have been found in approximately half of the HL cases analyzed. Gene expression profiles demonstrate that variations in the tumor microenvironment correlate with outcome.

SUGGESTED READINGS

Ansell SM, Lesokhin AM, Halwani A, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. New Engl J Med 2014 [Epub ahead of print].

Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomized, open-label, phase 3 non-inferiority trial. Lancet 2012;379:1791–1799.

Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 2010;363:640–652.

Gordon LI, Hong, F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol 2013;31:684–691.

Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. N Engl J Med 1998;329:1506–1514.

Meyer RM, Gospodarowicz MK, Connors JM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 2012;366:399–408.

Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 2012;30:2183–2189.