NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022

Featured Updates to the NCCN Guidelines

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  • 1 Stanford Cancer Institute;
  • | 2 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 3 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 4 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 5 Moffitt Cancer Center;
  • | 6 UCLA Jonsson Comprehensive Cancer Center;
  • | 7 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 8 The University of Texas MD Anderson Cancer Center;
  • | 9 UC Davis Comprehensive Cancer Center;
  • | 10 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 11 Fred & Pamela Buffett Cancer Center;
  • | 12 City of Hope National Medical Center;
  • | 13 Massachusetts General Hospital Cancer Center;
  • | 14 Mayo Clinic Cancer Center;
  • | 15 University of Michigan Rogel Cancer Center;
  • | 16 Duke Cancer Institute;
  • | 17 University of Wisconsin Carbone Cancer Center;
  • | 18 Fox Chase Cancer Center;
  • | 19 Fred Hutchinson Cancer Research Center/University of Washington;
  • | 20 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 21 O'Neal Comprehensive Cancer Center at UAB;
  • | 22 St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center;
  • | 23 Vanderbilt-Ingram Cancer Center;
  • | 24 UC San Diego Moores Cancer Center;
  • | 25 University of Colorado Cancer Center;
  • | 26 Abramson Cancer Center at the University of Pennsylvania;
  • | 27 Yale Cancer Center/Smilow Cancer Hospital;
  • | 28 Huntsman Cancer Institute at the University of Utah;
  • | 29 Roswell Park Comprehensive Cancer Center;
  • | 30 Memorial Sloan Kettering Cancer Center;
  • | 31 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; and
  • | 32 National Comprehensive Cancer Network.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-22-004-H01-P

Physician Assistants: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until April 10, 2023. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/91080; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: April 10, 2022; Expiration date: April 10, 2023

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • • Integrate into professional practice the updates to the NCCN Guidelines for Hodgkin Lymphoma

  • • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Hodgkin Lymphoma

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Richard T. Hoppe, MD, Panel Chair

Leo I. Gordon, MD, Panel Member

Monika Metzger, MD, Panel Member

Jennifer Burns, Manager, Guidelines Support, NCCN

Mallory Campbell, PhD, Oncology Scientist/Medical Writer, NCCN

Hema Sundar, PhD, Manager, Global Clinical Content, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

Ranjana H. Advani, MD, Panel Vice Chair, consulting fees from Bristol-Myers Squibb, Celgene Corporation, Genentech, Inc., Gilead Sciences, Inc., Incyte Corporation, Roche Laboratories, Inc., and sanofi-aventis U.S.; and grant/research support from Forty Seven, Inc.; Janssen Pharmaceutica Products, LP, Kura Oncology, Inc., Merck & Co., Inc., Millennium Pharmaceuticals, Inc., Cytier Therapeutics, Pharmacyclics, Regeneron Pharmaceuticals, Inc., and Seattle Genetics, Inc.

Philippe Armand, MD, PhD, Panel Member, scientific advisor for ADC Therapeutics, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, C4 Therapeutics, Epizyme, Genentech, Inc., Genmab, Merck & Co., Inc., and Regeneron Pharmaceuticals; grant/research support from Adaptive Biotechnologies, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Genentech, Inc., and IGM Biosciences, Kite; consulting fees from ADC Therapeutics, Enterome, Merck & Co., Inc., and Xencor; honorarium from Merck & Co.; and steering committee member for Tessa Therapeutics.

Alex F. Herrera, MD, Panel Member, consulting fees from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech, Inc., Karyopharm Therapeutics, Merck & Co., Inc., Regeneron Pharmaceuticals, Seattle Genetics, Inc., and Takeda Pharmaceuticals North America, Inc.; and grant/research support from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech, Inc., Gilead Sciences, Inc., Kite Pharma, Merck & Co., Inc., and Seattle Genetics, Inc.

Randa Tao, MD, Panel Member, consulting fees from Helsinn Therapeutics Inc., QED Therapeutics, Inc., and The Lynx Group, LLC.

Jane N. Winter, MD, Panel Member, honoraria from Celgene Corporation, Gilead Sciences, Inc., Janssen Pharmaceutica Products, LP, Merck & Co., Inc., Actinium Pharmaceuticals, Inc., and Epizyme; consulting fees from Novartis Pharmaceuticals Corporation and CVS Pharmacy; and grant/research support from Merck & Co., Inc.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.

This activity is supported by educational grants from AstraZeneca; BeiGene; Exact Sciences; Gilead Sciences, Inc.; GlaxoSmithKline; Lantheus Medical Imaging Inc.; Novartis; Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Astellas. This activity is supported by an education grant from Astellas and Seagen Inc. This activity is supported by a medical education grant from Karyopharm® Therapeutics. This activity is supported through an Independent Medical Education grant from Merck & Co., Inc.

Overview

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Most patients are diagnosed between 15 and 30 years of age, followed by another peak in adults aged ≥55 years. In 2022, an estimated 8,540 people will be diagnosed with HL in the United States and 920 people will die of the disease.1 The WHO classification divides HL into 2 main types: classical HL (cHL) and nodular lymphocyte–predominant HL (NLPHL).2 In Western countries, cHL accounts for 95% and NLPHL for 5% of all HL.

HL is among the most curable of malignancies with modern treatments, and a patient with newly diagnosed HL has a very high likelihood of being cured with appropriate treatment. In fact, cure rates for HL have increased so markedly that overriding treatment considerations often relate to long-term toxicity. Clinical trials still emphasize improvement in cure rates for patients with advanced disease, but the potential long-term effects of treatment remain important considerations.

These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy (RT) dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory (R/R) cHL.

Radiation Therapy

RT can be delivered with photons, electrons, or protons, depending upon clinical circumstances. RT alone was a standard treatment option for patients with early-stage HL for many decades; although RT is no longer used alone in cHL, it is still a useful part of frontline treatment, especially in patients with early-stage disease. However, the use of high-dose, large-field irradiation carries an increased long-term risk for cardiovascular disease, pulmonary dysfunction, and secondary cancers.3 Significant dose reduction to organs at risk (OARs; eg, lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle, soft tissue, salivary glands) can be achieved with advanced RT techniques, such as 4D CT simulation, intensity-modulated RT (IMRT)/volumetric modulated arc therapy, image-guided RT, respiratory gating, and deep inspiration breath hold.414 Involved-site RT (ISRT) and involved-node RT are used as alternatives to involved-field RT in an effort to further restrict the size of the RT fields and minimize the radiation exposure to adjacent uninvolved OARs and the potential long-term toxicities associated with radiation exposure.13,1517

Advanced RT techniques offer significant and clinically relevant advantages in specific instances to spare OARs and decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control. Although advanced RT techniques emphasize tightly conformal doses and steep gradients adjacent to normal tissues, the “low-dose bath” to normal structures such as the breasts must be considered when choosing the final RT technique.13 Therefore, target definition, delineation, and treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in tumor control. Initial diagnostic imaging with contrast-enhanced CT, MRI, PET, ultrasound, and other imaging modalities facilitate target definition.13 For optimal mediastinal treatment planning, organs or tissues to be contoured should include the lungs, heart, and cardiac subunits, including the coronary arteries (the left main, circumflex, left anterior descending, and right coronary arteries, with priority placed on sparing the proximal over distal portions of the arteries), the valves, and the left ventricle. Treatment planning for ISRT requires the use of CT-based simulation, and incorporation of PET and MRI often enhances the treatment planning. The optimized treatment plan for ISRT is designed with advanced RT techniques (conventional 3D conformal RT, proton therapy, or IMRT) using clinical treatment planning considerations of coverage and dose reductions for OARs.18

Randomized prospective studies to test these concepts are unlikely to be performed, because these techniques are primarily designed to decrease late effects, which usually develop ≥10 years after completion of treatment. Therefore, the NCCN Guidelines recommend that RT delivery techniques that are found to best reduce doses to OARs in a clinically meaningful manner without compromising target coverage should be considered in these patients, who are likely to enjoy long life expectancies following treatment.

Principles of RT Dose Constraints

Patients with hematologic malignancies typically receive far lower doses of RT than patients with epithelial or mesenchymal malignancies, and generally achieve more favorable long-term outcomes. More stringent dose constraints are recommended, often proportionally reduced from acceptable thresholds in other malignancies (HODG-D 3 and 4, pages 327 and 328, respectively). Doses to OARs should follow principles of ALARA (as low as reasonably achievable). In some scenarios, target coverage may require dose constraints to be exceeded if the OAR is within the planning target volume.

RT-induced secondary cancer is a late adverse effect of RT. Studies have reported that increasing RT dose is associated with an increased risk for second cancers without a safe threshold dose (linear no-threshold model), although the pattern of risk is less well understood than after low-dose exposure.19 Other contributing factors include age, environmental exposure, genetic risk factors, and radiation technique.20

RT dose constraints recommended for OARs, especially heart and lungs, are described in the following sections.

Heart

Multiple cardiac complications can develop from mediastinal RT, including pericarditis, arrhythmias, coronary artery disease, valvular heart disease (VHD), and cardiomyopathy/congestive heart failure.21,22 In addition to factors related to RT, the risk of cardiac events is also influenced by chemotherapy administration (eg, doxorubicin), preexisting cardiovascular disease, age, and other cardiac risk factors (eg, diabetes, hypertension, hyperlipidemia).21,2325 Although global heart metrics such as mean heart dose (MHD) are most commonly used to assess risk, there is an increasing recognition that RT dose fractionation to cardiac substructures must be accounted for (HODG-D 57, pages 329–331).

Mediastinal RT for lymphomas, relative to breast cancer and other thoracic malignancies, is characterized by radiation exposures to larger volumes of the heart and substructures, albeit at lower doses (20–40 Gy). The MHD has been related to the risk of cardiac events, although the volume of the whole heart exposed to RT is variable.26,27 In a case-control study of HL survivors who were treated mainly with anteroposterior/posteroanterior fields, using MHD as a measure of cardiac toxicity risk, van Nimwegen et al27 demonstrated an excess relative risk (RR) of 7.4% per Gy MHD. A significantly increased risk of coronary heart disease was reported among patients who received an MHD as low as 5 to 14 Gy (RR, 2.31) compared with an MHD of 0 Gy.27 This risk was increased for an MHD of ≥15 Gy (RR: 2.83 for 15–19 Gy, 2.9 for 20–24 Gy, and 3.35 for 25–34 Gy).27

The number of studies evaluating specific dose constraints for cardiac substructures is limited.21,28,29 Prescribed mediastinal RT dose was the only independent risk factor for VHD in a pediatric cohort study, and increasing mediastinal RT dose (especially >30 Gy) has been associated with an elevated risk of valvular dysfunction.28,29 In a large Dutch cohort of adult patients treated with mediastinal RT, the 30-year cumulative risks of VHD increased with increasing mean valvular RT doses (3% for ≤30 Gy, 6.4% for 31–35 Gy, 9.3% for 36–40 Gy, and 12.4% for >40 Gy) and there was no confounding effect of anthracycline chemotherapy on the risk of VHD.29 van Nimwegen et al21 demonstrated a relationship between heart failure and mean left ventricular dose. Chemotherapy was a clear confounder with regard to risk of heart failure. Among patients treated with anthracyclines, the 25-year cumulative risk of heart failure was 11.2% for mean left ventricular dose ≤15 Gy, 15.9% for 16–20 Gy, and 32.9% for ≥21 Gy.

RT dose constraints for coronary arteries is a work in progress, and only a few studies have evaluated the effect of coronary RT dose on the risk of coronary artery disease.3033 In a large retrospective study of patients with non–small cell lung cancer (NSCLC) treated with thoracic RT, major adverse cardiac events were found to be associated with the volume of the left anterior descending coronary artery receiving 15 Gy (V15 Gy ≥10%).33 Although there is no robust evidence to recommend specific guidance on dose constraints to specific coronary arteries in patients with lymphomas, limited available evidence supports the general notion of a dose–response effect in the clinical range of lymphoma RT prescriptions.

NCCN Recommendations

Although the data regarding cardiac constraints for modern RT for lymphomas are imperfect, the panel recommends that the MHD be kept as low as possible, ideally <8 Gy, though in some patients a higher dose will be necessary given lymphoma extent. The panel recognizes that nearly all patients with lymphoma receive anthracycline-based chemotherapy, even though cumulative chemotherapy doses in modern practice tend to be lower than in historical cohorts. Whole-heart irradiation increases the risk of constrictive pericarditis, especially with whole-heart RT doses >15 Gy34; therefore, it is recommended that MHD should rarely exceed 15 Gy. This may be reconsidered if patients are being treated in the second-line setting with curative intent, wherein larger RT doses are necessary. Mean left ventricular dose should not exceed 8 Gy, though in some circumstances up to 15 Gy may be necessary. Aortic and mitral valve doses should be <25 Gy, although lower doses would be optimal. Given that tricuspid and pulmonic valves may be less affected OARs, it is recommended that doses <30 Gy be administered. Constraints to coronary arteries are less well defined,35 but should be as low as possible in terms of dose, volume, and length.

Lungs

Mediastinal RT-related pulmonary toxicity is primarily radiation pneumonitis, and other complications, including symptomatic fibrosis or bronchopleural fistula, have been encountered rarely. Radiation pneumonitis is a clinical diagnosis consisting of dry cough, dyspnea, and occasionally low-grade fevers, and must be distinguished from other entities, including drug-induced (especially bleomycin) pneumonitis, infectious pneumonia, acute bronchitis, and pulmonary embolism. Pulmonary complications can also arise from systemic modalities, such as brentuximab vedotin (BV) and immunotherapy.

The most important risk factors for radiation pneumonitis are lung dose–volume metrics, including mean lung dose (MLD), V20 Gy, and V5 Gy. Such metrics have been associated with pneumonitis risk in both epithelial36 and hematologic malignancies.37 For epithelial malignancies such as NSCLC, it is generally recommended that MLD be <20 Gy and V20 Gy be <35%. In most circumstances, given the lower doses used in lymphoma management, much lower doses are generally achievable with careful planning.

NCCN Recommendations

The panel recommends limiting MLD to <13.5 Gy and V20 Gy to <30%, although RT to the lungs in most patients with lymphoma can be maintained below these thresholds (HODG-D 8, page 332). In cases for which IMRT or volumetric arc techniques are appropriate, limiting the V5 Gy to <55% is recommended.

Management of Stage III–IV cHL

Current management of stage III–IV disease involves treatment with chemotherapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) is the preferred chemotherapy regimen based on several randomized clinical trials that have failed to show a survival benefit for more intensive regimens (HODG-5, page 324).3841 Results of the important RATHL trial demonstrated that the omission of bleomycin from the ABVD regimen in patients with negative interim PET scan results (Deauville score 1–3) after 2 cycles of ABVD resulted in a lower incidence of pulmonary toxicity compared with continued ABVD, without impacting efficacy.42

Other options for advanced-stage disease include BV-AVD (doxorubicin/vinblastine/dacarbazine) × 6 cycles or escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) × 2 cycles followed by restaging with PET (and additional cycles of escalated BEACOPP [total of 4 or 6 cycles] or A(B)VD × 4 cycles, depending on the Deauville score at interim restaging) for select patients aged <60 years with an International Prognostic Score (IPS) ≥4 (HODG-5, page 324).4346

Results of the ECHELON-1 trial showed that BV-AVD had superior progression-free survival (PFS) compared with ABVD in the treatment of patients with stage III–IV disease.43,44 In this trial, patients with previously untreated stage III or IV cHL were randomized to receive either ABVD (n=670) or BV-AVD (n=664).43 Patients received 6 cycles of chemotherapy without treatment adaptation based on interim restaging. The 5-year follow-up data confirmed a PFS benefit for BV-AVD compared with ABVD and was consistent in all patient subgroups independent of disease stage, age, and IPS.44 At a median follow-up of 61 months, the 5-year PFS rates in the BV-AVD and ABVD groups were 82% and 75%, respectively (P=.0017).

A prespecified subgroup analysis confirmed that BV-AVD was associated with consistent improvement in PFS at 3 years among patients in high-risk subgroups, as assessed by the investigator (hazard ratio [HR], 0.723 for patients with stage IV disease; P=.032; HR, 0.588 for patients with IPS 4–7; P=.012).47 The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% in the BV-AVD group compared with 65.7% for ABVD group. Patients in the high‐risk subgroups did not experience greater incidences of treatment-related adverse events (trAEs) than the total population. However, to date there is no clear benefit of BV-AVD over ABVD in patients aged >60 years, as confirmed by the prespecified subgroup analyses with extended follow-up for the overall population. The 5-year PFS rates for BV-AVD were similar to those for ABVD among older patients with stage III (HR, 1.051; P=.917) or stage IV disease (HR, 0.722; P=.291).48

Although the incidence of pulmonary toxicity was lower in the BV-AVD arm due to the elimination of bleomycin, there was a higher rate of peripheral neuropathy (19% vs 9% in the ABVD arm) and febrile neutropenia (19% vs 11%, respectively), mandating the use of growth factor support with this regimen.43,44 Furthermore, the rate of pulmonary toxicity in the control group does not reflect that of modern management, given that bleomycin may be omitted in the vast majority of patients after the first 2 cycles (see earlier discussion of the RATHL trial42). Upon longer follow-up, continued resolution or improvement of peripheral neuropathy was seen in both groups (85% of patients in the BV-AVD arm vs 86% for those in the ABVD arm).44

Based on the updated safety and efficacy data from the ECHELON-1 trial,43,44 BV-AVD is now included in the NCCN Guidelines as a category 2A recommendation for all patients with stage III or IV disease, but needs to be used with caution in patients with neuropathy (HODG-6, page 325). Furthermore, its benefit is not clear in patients aged >60 years and its toxicity in this age group should be considered. Long-term results of this trial are awaited, especially with respect to potential differences in survival. BV-AVD is initially administered for 6 cycles, followed by restaging with PET.44 If PET/CT is performed before completion of 6 cycles, a biopsy is recommended in patients with a Deauville score of 5. Therapy should be reevaluated for positive biopsies. At the completion of therapy, patients with a Deauville score of 1–3 should be managed as described for follow-up and monitored for relapse/late effects. ISRT to initially bulky or PET-positive sites may be considered for patients with a Deauville score of 4–5. Alternatively, a biopsy may be considered for patients with a Deauville score of 5, and if positive, alternative therapy for refractory disease should be pursued.

It must be emphasized that the ECHELON-1 trial design was not PET-adapted; consequently, patients treated with ABVD who could have benefited from dose escalation according to current practices, or for whom bleomycin could have been omitted, were continued on ABVD. Consequently, the superiority of BV-AVD over PET-adapted ABVD according to the RATHL trial has not been established.

Management of R/R cHL

Second-line systemic therapy followed by high-dose chemotherapy and autologous stem cell rescue (HDT/ASCR) with or without RT is the recommended treatment approach.4952 Maintenance therapy with BV (for 1 year) following HDT/ASCR can be considered for patients with high risk for relapse as defined by the AETHERA trial (defined as those having primary refractory disease, duration of first complete response <1 year, or relapse with extranodal or advanced-stage disease).53

ICE (ifosfamide/carboplatin/etoposide) and DHAP (dexamethasone/cisplatin/high-dose cytarabine) are the most commonly used systemic therapy regimens. Gemcitabine-based combination regimens, such as GVD (gemcitabine/vinorelbine/pegylated liposomal doxorubicin),54 IGEV (ifosfamide/gemcitabine/vinorelbine),55 GCD (gemcitabine/cisplatin/dexamethasone),56,57 and GEMOX (gemcitabine/oxaliplatin),58 have also been effective for R/R HL. However, none of these regimens has been studied in randomized trials. Bendamustine, lenalidomide, and everolimus as single agents have also shown activity in patients with R/R HL.5961 BV, a CD30-directed antibody–drug conjugate, has demonstrated activity in patients with R/R CD30-positive lymphomas (as monotherapy or in combination regimens).6266

Checkpoint inhibitors including PD-1–blocking monoclonal antibodies (eg, nivolumab or pembrolizumab) have also demonstrated activity in patients with R/R PD-1–positive lymphomas (as monotherapy or in combination regimens).6775

In a phase II study (CheckMate 205) of 80 patients with R/R cHL pretreated with both HDT/ASCR and BV, at a median follow-up of 8.9 months nivolumab monotherapy induced an objective response rate of 66.3% (95% CI, 54.8%–76.4%), as determined by an independent radiologic review committee.68 Extended follow-up of the CheckMate 205 trial analyzed the safety and efficacy of nivolumab in patients with R/R cHL according to treatment history: BV-naïve, BV after HDT/ASCR, or BV before and/or after HDT/ASCR.69 The objective response rate was 69% (95% CI, 63%–75%) overall and 65% to 73% in each cohort, with a median duration of response of 16.6 months (95% CI, 13.2–20.3 months).69 Nivolumab is included in the NCCN Guidelines as an option for patients with R/R cHL after ≥2 lines of systemic therapy (HODG-C 3, page 326).

In a phase III trial (KEYNOTE-204), pembrolizumab monotherapy versus BV was evaluated on the parameters of safety and efficacy in adults with R/R cHL (patients who were ineligible for transplant or those who experienced relapse after autologous hematopoietic cell transplant; 151 patients were randomly assigned to pembrolizumab and 153 to BV).74 At second interim analysis, PFS (primary endpoint) was 13.2 months for pembrolizumab and 8.3 months for BV (P=.0027).74 Overall survival was not analyzed in interim analysis. trAEs were observed in 74% of patients receiving pembrolizumab and 77% of patients receiving BV. The most common grade 3–5 trAEs were pneumonitis (4% in the pembrolizumab group vs 1% in the BV group), neutropenia (2% vs 7%, respectively), decreased neutrophil count (1% vs 5%, respectively), and peripheral neuropathy (1% vs 3%, respectively).74 Serious trAEs were observed in 16% of patients receiving pembrolizumab and 11% of patients receiving BV.74 Pembrolizumab is included in the NCCN Guidelines as a second-line therapy option for R/R disease in patients who are not eligible for transplant. It is also included as an option for patients with R/R cHL after ≥2 lines of systemic therapy (HODG-C 3, page 326).

Nivolumab in combination of BV was evaluated as an option for R/R HL prior to HDR/ASCR.71 In a phase I/II study of 91 patients with R/R cHL, the combination of nivolumab with BV resulted in an objective response rate of 85% (67% complete response). At a median follow-up of 34 months, the estimated 3-year PFS and overall survival rates were 77% (91% for patients who underwent HDT/ASCR directly after study treatment with BV + nivolumab) and 93%, respectively.71 Pembrolizumab in combination with GVD also has demonstrated very high activity as second-line treatment in transplant-eligible patients with R/R cHL, resulting in a complete response rate of 95%.75 At a medium follow-up of 13.5 months, all patients who had undergone HDR/ASCR had achieved remission. BV + nivolumab and GVD + pembrolizumab are included in the NCCN Guidelines as an option for second-line and subsequent therapy for patients with R/R cHL (HODG-C 3, page 326).

Summary

RT is still a useful part of frontline treatment for HL, especially in patients with early-stage disease, and RT delivery techniques designed to reduce doses to OARs without compromising target coverage should be considered for these patients. Chemotherapy followed by restaging with PET/CT is recommended for patients with stage III–IV cHL. Second-line systemic therapy followed by HDT/ASCR with or without RT is recommended for patients with R/R cHL. Maintenance therapy with BV following HDT/ASCR can be considered for patients at high risk for relapse. Nivolumab or pembrolizumab (as monotherapy or in combination regimens) are also included as options for R/R disease in appropriate patients. Long-term follow-up with careful monitoring for late trAEs and counseling about issues of survivorship should be an integral part of management of patients with HL. Consistent with NCCN philosophy, participation in clinical trials is always encouraged.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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