Hodgkin Lymphoma (HL)

Background

• HL is an uncommon, highly curable B-cell hematologic malignancy originating in the lymphatic system.
• HL has a bimodal age distribution, and most commonly affects adolescents and young adults aged 15-35 years. Less commonly, HL affects adults ≥ 55 years old.
• Globally, the age-standardized HL incidence was 0.98 per 100,000 persons per year in 2020.
• HL is classified into classic HL (cHL) (most common) and nodular lymphocyte-predominant HL (NLPHL) histologic types. cHL is further subdivided into nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted subtypes.
• Most common risk factors include Epstein-Barr virus (EBV) infection, a family history of HL, and immunosuppressive and immune-related conditions, such as, HIV infection and a history of solid organ transplantation.
• Prognosis of newly diagnosed HL is generally excellent, with a cure rate ≥ 90% for early-stage disease, and 70%-80% for advanced-stage disease.
• Adverse prognostic factors depend on the clinical stage. In stage I-II disease, factors include elevated erythrocyte sedimentation rate, presence of B symptoms, presence of large mediastinal mass, multiple nodal involvement, bulky lymphadenopathy, and extranodal involvement. In stage III-IV disease, factors include older age, low level of albumin, low level of hemoglobin, male sex, leukocytosis, and lymphocytopenia.
• Because of the generally favorable prognosis of patients with newly diagnosed HL, decisions on management strategies should include consideration for the minimization of therapy-related complications, especially for patients with early- or intermediate-stage disease.

Evaluation

• Suspect a diagnosis of HL in patients presenting with painless supradiaphragmatic lymphadenopathy, systemic B symptoms, severe or chronic pruritus, and/or alcohol-induced pain or intolerance.
• Establish the diagnosis ideally with an excisional biopsy of the involved lymph node, using histopathologic analysis and immunohistochemical evaluation (Strong recommendation). Core needle biopsy may be adequate for a diagnosis in some cases, whereas fine needle aspirate is not sufficient for a diagnosis (Weak recommendation).
• For staging and risk stratification:
  • Perform a complete history and physical (Strong recommendation).
  • Perform blood tests including complete blood count with differential, erythrocyte sedimentation rate, and comprehensive metabolic panel (Strong recommendation).
  • Perform testing to detect HIV, hepatitis B virus, and hepatitis C virus infection (Strong recommendation).
  • Perform imaging studies, including whole body fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) with contrast-enhanced CT (either as a separate modality or integrated with FDG-PET/CT) (Strong recommendation).
• Obtain a pregnancy test for patients of childbearing age prior to chemotherapy or radiation therapy (Strong recommendation). If the patient is pregnant, consult with obstetrical specialists in regard to management strategies (Strong recommendation).
• Assess the risk of therapy-induced complications, including pulmonary function tests if bleomycin-based chemotherapy is being considered and evaluation of cardiac function if anthracycline-based chemotherapy is being considered (Strong recommendation).

Management

Classic Hodgkin Lymphoma (cHL)

Initial Management of cHL

• Management decisions depend on multiple factors, including the disease risk (clinical stage and the presence of unfavorable risk factors), age, sex, a family history of cancer, the presence of comorbidities, and the sites of disease involvement (such as, mediastinum or axilla).
• Planning of therapies should aim to minimize potential early and late treatment-related complications.
• Regardless of subtype, review options of fertility preservation in patients of childbearing age (such as, oocyte preservation in women and semen cryopreservation in men) and treatment strategies before the initiation of treatment in appropriate patients if possible (Strong recommendation).
• Consider enrollment in clinical trials for all patients with HL (Weak recommendation).
• As preferred initial therapy for cHL stage IA/IIA favorable disease or IB/IIB unfavorable disease, offer 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (Strong recommendation for stage IA/IIA favorable disease; Weak recommendation for stage IB/IIB unfavorable disease), followed by restaging and a response assessment with FDG-PET/CT using the Deauville score (Weak recommendation).
• As preferred initial therapy for cHL stage III-IV disease, offer 2 cycles of ABVD or brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) (Strong recommendation), followed by restaging and a response assessment with PET/CT using the Deauville score (Weak recommendation).
• Additional management may be modified based on interim PET/CT findings and the patient population.
• Alternative regimen intensity may be appropriate for older adults > 60 years old, for children or adolescents, or for patients during pregnancy.
• Long-term, routine follow-up is generally necessary to detect disease recurrence and late complications, such as, cardiovascular complications, secondary malignancies, and thyroid dysfunction (Weak recommendation).

Management of Relapsed or Refractory cHL

• For patients with suspected relapsed or refractory disease, a biopsy to confirm histologic relapse and staging is recommended prior to the initiation of therapy (Weak recommendation).
• For most patients, second-line therapy is followed by a response assessment with PET/CT. Subsequent management options depend on whether the disease is metabolically positive (Deauville score ≥ 4) or negative (Deauville score ≤ 3) on the PET/CT.
• For fit adults ≤ 60 years old, the primary management option is second-line induction therapy followed by high-dose chemotherapy plus autologous hematopoietic stem cell transplantation (HSCT) with or without radiation therapy (Strong recommendation).
• For adults > 60 years old, consider enrollment in a clinical trial (Weak recommendation). If management is outside of a clinical trial, consider palliative therapy with brentuximab vedotin-based therapy, checkpoint inhibitor-based therapy, chemotherapy, or involved-site radiation therapy (ISRT) only (Weak recommendation).

Nodular Lymphocyte-predominant Hodgkin Lymphoma (NLPHL)

Initial Management of NLPHL

• Management decisions depend on multiple factors, including the disease risk (clinical stage and the presence of unfavorable risk factors), age, sex, a family history of cancer, the presence of comorbidities, and the sites of disease involvement (such as, mediastinum or axilla).
• Planning of therapies should take into account potential early and late management-related complications.
• For patients with nonbulky stage IA or contiguous stage IIA disease, either offer ISRT as the preferred management (Strong recommendation for stage IA favorable disease; Weak recommendation for other stages of disease) or, for stage IA disease with completely excised solitary lymph node, consider observation (Weak recommendation).
• For patients with stage IB or IIB disease, bulky IA disease, or bulky or noncontiguous stage IIA disease, consider either rituximab (or biosimilar)-based chemoimmunotherapy plus ISRT (Weak recommendation).
• For patients with stage III-IV disease, management options include:
  • rituximab (or biosimilar or subcutaneous rituximab)-based combination chemoimmunotherapy with or without ISRT (Weak recommendation),
  • rituximab (or biosimilar or subcutaneous rituximab) monotherapy (Weak recommendation),
  • local radiation therapy for palliation of locally symptomatic disease (Weak recommendation)
  • observation for asymptomatic disease, and in certain circumstances, may consider chemotherapy plus rituximab (Weak recommendation)
• After initial management, additional management depends on restaging and response assessment using PET/CT.
• Long-term, routine follow-up is generally necessary to detect recurrence, transformation to large cell lymphoma, and late complications, such as, cardiovascular complications, secondary malignancies, and thyroid dysfunction (Weak recommendation).

Management of Relapsed or Refractory NLPHL

• For patients with biopsy-confirmed refractory or relapsed disease, management options include observation, rituximab monotherapy, rituximab (or biosimilar or subcutaneous rituximab)-based chemoimmunotherapy with or without ISRT, or ISRT alone (Weak recommendation).
• For patients with transformation to aggressive B-cell lymphoma, consider management as relapsed or refractory diffuse B-cell lymphoma (see Diffuse Large B-cell Lymphoma for additional information).