Overview
Classic Hodgkin lymphoma (CHL) is a malignancy involving lymph nodes and the lymphatic system and is generally characterized by the presence of large binucleate or multinucleated neoplastic cells or mononuclear variants, (collectively termed Hodgkin Reed-Sternberg [HRS] cells) in a background of benign inflammatory cells.1 Most patients are diagnosed between 15 and 30 years of age, followed by another peak in adults aged 55 years or older. Although the exact etiology is unknown, known risk factors for HL include prior infection with Epstein Barr virus (EBV) and immunocompromising conditions, including immunosuppression after organ transplantation or infection with HIV.2–4
The WHO classification divides HL into 2 main types: CHL and nodular lymphocyte-predominant HL.4 CHL is divided into 4 subtypes: nodular sclerosis CHL; mixed cellularity CHL; lymphocyte-depleted CHL; and lymphocyte-rich CHL.4 CHL is characterized by the presence of HRS cells in an inflammatory background and expresses CD30, whereas nodular lymphocyte-predominant HL lacks HRS cells but is characterized by the presence of lymphocyte-predominant cells, sometimes termed popcorn cells. It differs from CHL as it is negative for CD30 and positive for CD20. Most cases of childhood HL are CHL; nodular lymphocyte-predominant HL only accounts for 5%–10% of childhood HL.1 This rarer subtype is not included in the current Pediatric HL NCCN Guidelines and will be included in future versions.
In 2021, an estimated 8,830 people will be diagnosed with HL in the United States and 960 people will die of the disease.5 In adolescents (aged 15–19 years), HL is the most commonly diagnosed cancer6 and it is estimated that 4,200 adolescents and young adults (AYAs) aged 15 to 39 years of age were diagnosed with HL in 2020, with 800 of those cases being aged 15 to 19 years.7 The incidence is less common in children aged 5 to 14 years; in 2014, a report estimated that 380 children will be diagnosed with HL each year.6
The past few decades have seen significant progress in the management of pediatric patients with HL, with estimated 5-year survival rates greater than 98% after treatment with chemotherapy alone or combined with radiotherapy (RT).8,9 However, the potential long-term effects of treatment remain an important consideration.8,9
The NCCN Clinical Practice Guidelines Oncology (NCCN Guidelines) for Pediatric HL were developed as a result of meetings convened by a multidisciplinary panel of pediatric HL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines currently focus on clinical staging of CHL, and treatment strategies are adapted according to risk. Given the complexity of staging for HL and nuances of treatment regimens and response criteria, the NCCN Pediatric HL Panel recommends a consultation with centers participating in pediatric cooperative group trials. Consistent with NCCN philosophy, participation in clinical trials is always encouraged.
The panel considers the term pediatric to include any patient aged 18 years of age and younger, and the recommendations in the NCCN Guidelines may extend to adolescent and young adult (AYA) patients up to 39 years of age. Across treatment centers, practice patterns vary with regard to AYA patients in terms of whether patients with HL are treated primarily by pediatric or adult oncologists. These NCCN Guidelines are intended to apply to pediatric patients and may also apply to AYA patients treated in an adult oncology setting.
Diagnosis and Workup for CHL
For evaluation and initial workup of CHL, the panel recommends that an excisional lymph node biopsy generally be performed (see PHL-1, page 734). Immunostaining for CD30, CD15, CD20, and CD3 is recommended for CHL. Evaluation of an expanded panel of markers (ie, CD45, CD79a, ALK, MUM1, OCT2, and BOB1) should be considered in cases with equivocal or imperfect morphologic features, or to exclude other entities in the differential diagnosis. The HRS cells of CHL express CD30 in all patients, CD15 in most patients, and are usually negative for CD45 and CD3. CD20 may be detectable in a minority of cases. Cases of EBV+ CHL may benefit from additional studies such as EBV serology and evaluation for underlying immunodeficiency. For additional information, see “Principles of Pathology” in the algorithm (see PHL-B 1 and 2 of 3, pages 742 and 743).
The workup should include a thorough history and physical examination, including determination of one or more B symptoms (unexplained recurrent fevers >38°C within the last month; drenching night sweats within the last month; weight loss of >10% of body weight within 6 months of diagnosis), and examination of lymphoid regions and spleen. Other essential components of the workup include standard laboratory tests (complete blood count [CBC] with differential; erythrocyte sedimentation rate [ESR] and/or C-reactive protein [CRP]; and a comprehensive metabolic panel). A pregnancy test should be performed before women of childbearing age undergo radiologic testing and/or treatment. HIV and hepatitis B and C testing is encouraged for patients with risk factors for HIV or unusual disease presentations (see PHL-1, page 734).
PET scans are essential for initial staging and for evaluating residual masses for response during therapy and at the end of treatment10 (see “Principles of Imaging,” PHL-C 1 of 2, page 744, and “Principles of Staging,” PHL-D 1 and 2 of 2, pages 745 and 746 in the algorithm). For staging and risk assessment, diagnostic imaging should be done before initiating chemotherapy or steroids whenever possible including: PET/CT or PET/MRI scans (whole-body); diagnostic contrast-enhanced CT of the neck, chest, abdomen, and pelvis; or CT of chest and MRI of the neck, abdomen, and pelvis. PET scans should be assessed by a nuclear diagnostic radiologist experienced in reading Deauville scores for PET-adapted therapy. A posterior-anterior chest X-ray is recommended to determine bulk of disease (mediastinal mass) or as defined by a clinical trial. Consultation with a radiation oncologist is strongly recommended to assist in determining treatment options, assessment of response and application of criteria to determine the need for radiation therapy.
PET interpretation is very challenging given the high sensitivity without specificity. In cases of PET positivity where sites of disease are not consistent with usual presentation of HL or if there are unusual disease presentations (ie, HIV), additional evaluation may be needed to stage the patient. If PET is negative for anatomic lesions of concern, a biopsy may be considered, but is not the standard of care.
In most cases, if the PET/CT displays a homogeneous pattern of marrow uptake, which is thought to be secondary to cytokine release,11,12 bone marrow involvement is not assumed. If there are multifocal skeletal PET lesions without cortical destruction on CT, marrow involvement may be assumed and a bone marrow biopsy is not needed to confirm involvement.13 In select cases, if there are cytopenias and the PET scan is negative, a bilateral bone marrow biopsy may be considered.
If anthracycline-based chemotherapy is indicated, an echocardiogram is recommended Pulmonary function tests (PFTs), including diffusing capacity of the lungs for carbon monoxide, are recommended for patients receiving bleomycin-based chemotherapy. In general, an FEV1/FVC of at least 60% is acceptable for bleomycin use, unless it is lower due to a large mediastinal mass from HL. For children who are unable to cooperate for PFTs, the criteria for bleomycin use are: no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry reading of >92% on room air.
The panel recommends referral to a fertility specialist for discussion regarding fertility preservation options (eg, semen cryopreservation in male patients, ovarian tissue or oocyte cryopreservation in female patients) before the start of therapy and referrals for counseling as needed that address smoking cessation or substance abuse disorders, and psychosocial concerns. For additional recommendations, see the NCCN Guidelines for Supportive Care (available at NCCN.org).
Clinical Staging and Risk Stratification
Physical examination and diagnostic imaging evaluations are used to designate the clinical stage.1 The most widely used staging scheme for both pediatric and adult HL is the Ann Arbor Staging, which may include the Cotswolds modification for the prognostic significance of bulky disease1,14,15 Staging is generally defined as follows15:
- • Stage I: One nodal group or lymphoid organ (eg, spleen, thymus and Waldeyer’s Ring)
- • Stage II: Two or more nodal groups on the same side of the diaphragm
- • Stage III: Nodal groups on both sides of the diaphragm
- • Stage IV: Disseminated involvement of one or more extralymphatic organ (eg, lung, bone) with or without any nodal involvement
Additional substaging variables include these terms:
- • A: Asymptomatic
- • B: Presence of one or more B symptoms
- • X: Bulky nodal disease which is nodal mass greater than one-third of intrathoracic diameter on a CXR or as defined by the protocol. Note: pediatric protocols have also defined bulk disease as contiguous extramediastinal nodal mass greater than 6 cm in the longest transverse diameter or craniocaudal dimension, and EuroNet defines bulk as >200 mL (See PHL-D 2 of 2, page 746).
- • E: Involvement of extra lymphatic tissue on one side of the diaphragm by limited direct extension from an adjacent nodal site*
*Note: The Ann Arbor staging system is in need of revision as it does not fully represent the current practice in staging pediatric Hodgkin lymphoma. Refer to the original protocol for appropriate staging of “E-lesions.” Many protocols today define an E-lesion” as extension from a site of involvement into a surrounding tissue or organ and this does not always indicate stage IV disease. Involvement of an extranodal site that is extralymphatic and does not arise from direct extension is considered to be stage IV disease. The distinction between stage IV disease and E-lesions is not applied uniformly and remains an area in need of international harmonization.
Currently, there is no uniform risk stratification for pediatric HL although several factors are considered to confer a poor prognosis depending on the clinical trial including one or more B symptoms, mediastinal and/or peripheral lymph node bulk, extranodal disease, number of nodal sites, Ann Arbor stage, serum markers for inflammation, gender, and response to initial chemotherapy.1 To facilitate the interpretation and comparison of global clinical trials, an international collaborative effort was developed: the Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) working group.16 As the SEARCH effort for CAYAHL continues, so will the evolution of harmonized risk stratification for pediatric HL.9
There are several cooperative groups, including the Children’s Oncology Group (COG) (which resulted from a merging of the Pediatric Oncology Group and Children’s Cancer Group) and the European Network for Pediatric Hodgkin Lymphoma (EuroNET-PHL).9 In the guidelines, the panel has summarized clinical stage and associated risk groups (see “Clinical Staging of Classic Hodgkin Lymphoma,” PHL-2 in the algorithm, page 735) and notes where the risk groups varied for inclusion onto each trial. Due to the evolving treatment regimens that build on the success of previous trials, enrollment in a clinical trial is always preferred. In addition, given the rarity of these patients and the challenges of staging, the panel recommends considering consultation with a center of expertise for patient management as needed.
Principles of Imaging
Clinical management of pediatric patients with CHL involves initial treatment with chemotherapy and assessment of treatment response with PET to determine the need for RT.17–19
Given the avidity of pediatric lymphomas for FDG,18 the Deauville criteria were defined for the interpretation of PET scans based on the visual assessment of FDG uptake in the involved sites (see Deauville Criteria Table in “Principles of Staging,” PHL-D 2 of 2, page 746). These criteria use a 5 point-scale (5PS) to determine the FDG uptake in the involved sites relative to that of normal structures such as the mediastinum and the liver.20–22 In the 5-PS (Deauville criteria), scores of 1 to 4 refer to initially involved sites. A score of 5 refers to an initially involved site and/or new lesions related to lymphoma,21,22 These criteria vary across different protocols because they have yet to be validated in a large pediatric trial. However, interim or end-of-treatment PET scans with a score of 1, 2, or 3 are generally considered “negative” and PET scans with a score of 4 and 5 are considered “positive”.23 A score of 4 can be difficult to assess when FDG uptake in mediastinal masses cannot clearly be differentiated from thymic uptake or inflammatory reactions,20,24,25 and treatment decisions in these cases will require clinical judgment. In addition, Deauville 4 may represent just a single area of persistent disease or failure to respond in any site. The 5PS (Deauville criteria) has been validated in international multicenter trials for PET-guided interim response assessment and risk-adapted-therapy in adult patients with HL.
PET imaging is important as a baseline measurement before therapy to determine the initial sites of involvement and to perform an early response assessment (often after the initial 2 cycles of chemotherapy).10,11 The panel recommends diagnostic contrast-enhanced CT or MRI to adequately evaluate all sites of involvement, and PET/CT or PET/MRI for interim and end-of-therapy assessments. In addition, the panel recommends waiting for at least 8 to 12 weeks after the end of RT to perform an end of therapy PET scan to minimize false-positive results (see PHL-C 1 of 2, page 744).
In some cases, routine surveillance scans in the first year after completion of therapy may have utility; however, they are recommended to be limited thereafter. During follow-up, scans should only be obtained if there is clinical concern for relapse, or for up to 2 years.
Principles of RT
RT can be delivered with photons, electrons, or protons, depending on clinical circumstances (see PHL-F 1, 2, and 3 of 4, pages 748–750). 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 in choosing the final RT technique. 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.
Data from single institution studies have shown that significant dose reduction to organs at risk (eg, lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid arteries, bone marrow, stomach, muscle, soft tissue and salivary glands) can be achieved with advanced RT planning and delivery techniques such as 4-dimensional CT simulation, intensity-modulated RT/volumetric modulated arc therapy, image-guided-RT, respiratory gating, deep inspiration breath hold, or proton therapy.26–28 These techniques offer significant and clinically relevant advantages in specific instances to spare organs at risk and decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control. However, the panel notes that randomized prospective studies to test these concepts are unlikely to be performed since these techniques are designed to decrease late effects, which usually develop ≥10 years after completion of treatment. Therefore, the guidelines recommend that RT delivery techniques that are found to best reduce the doses to the organs at risk in a clinically meaningful manner without compromising target coverage should be considered in these patients, who are likely to enjoy long life expectancies after treatment.
Involved-site RT (ISRT) is recommended as the appropriate field for HL and can safely replace involved field RT (IFRT) or modified IFRT from earlier trials. ISRT targets the originally involved nodal sites and possible extranodal extension (which generally defines a smaller field than the classic IFRT),29 and is intended to spare the adjacent uninvolved organs (such as lungs, bone, muscle, or kidney) when lymphadenopathy regresses after chemotherapy. Treatment planning for ISRT requires the use of CT-based simulation, and additional imaging techniques such as PET and MRI often enhance the treatment planning.
For patients with low or intermediate risk disease, the panel recommends an RT dose of 21 Gy to all sites of disease. Sites of slow response (usually defined with specific anatomic and/or PET criteria) can receive a boost of up to 9 Gy (total dose, 21–30 Gy). Sites of partial response (PR) should receive a boost of 9–19 Gy (total dose, 30–40 Gy). For patients with high-risk disease, the panel discourages using regimens that require ISRT to all sites of disease. Instead, for bulky disease, a dose of 21 Gy may be considered. The RT doses recommended for sites of slow response and sites of PRs in the low or intermediate risk disease setting are same in this context. The panel notes that residual site RT should only be used when dictated by the protocol or as a boost following standard ISRT.
For patients with relapsed or refractory disease, if no high-dose therapy (HDT) or autologous stem cell rescue (ASCR) is planned, an RT dose of 30 Gy is recommended. If HDT/ASCR is planned, an RT dose of 30 Gy to relapsed or refractory sites may be used typically posttransplant, with a consideration of 21 Gy to initial sites that are no longer present with active disease. If PET positive (Deauville 4–5) after several lines of therapy, RT may be considered to achieve metabolic complete response (CR) before transplant. Boost RT doses of 10–15 Gy (total dose of 40–45 Gy) to PET positive sites may be considered.
Management of CHL
In this section, data from select clinical trials that are recommended in the NCCN Guidelines are reviewed to provide a rationale for their inclusion.
Low-Risk CHL
Approximately 26% to 34% of children and adolescents with HL present with low-risk disease.30 Outcomes for children and adolescents with low-risk HL are excellent; as such, recent trials are focused on modifying treatment (ie, reduction or elimination of specific chemotherapeutic agents or RT) to reduce risk of late effects.30 For instance, the German Society of Pediatric Oncology and Hematology Hodgkin’s Disease (GPOH-HD) study series has demonstrated that RT can be eliminated from a combined modality treatment scheme for TG-1 patients who experience complete remission after chemotherapy [GPOH-HD-95 trial].31
In the GPOH-HD-2002 study, the main goal was to replace a component of chemotherapy (ie, procarbazine with etoposide and dacarbazine) to decrease gonadal toxicity in boys with HL.32 In this trial, all patients were aged <18 years (n=573); for induction, boys (n=287) received 2 courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin), and girls (n=286) received 2 courses of OPPA (vincristine, procarbazine, prednisone, and doxorubicin).32 After chemotherapy, all patients received IFRT to 19 Gy except patients in TG-1 stage who were in CR (residual tumor volume ≤95% and ≤2 mL of the initial volume). In TG-1, the event-free survival (EFS) was 92% ± 2.0%, with no significant impact of RT on EFS.32 This trial confirmed findings from GPOH-HD-95 that RT could be eliminated in TG-1 patients who experience CR after chemotherapy.31,32
Building on the GPOH-HD studies, an international intergroup study for CHL in children and adolescents (EuroNET-PHL C1) aimed to demonstrate a 90% 5-year EFS in PET-negative patients (TG-1) after 2 cycles of OEPA, and demonstrate that dacarbazine can safely replace procarbazine in consolidation chemotherapy (COPP vs COPDAC) in TG-2 and TG-3 stages without impairing treatment.33 In a report from an interim analysis, the 4-year overall survival (OS) and EFS was 98% and 88%, respectively.33 The EFS in TG-1, TG-2 and TG-3 was 87.5%, 91%, and 86.6%, respectively (P=.08). The EFS in patients with or without RT was 88% and 87%. In addition, the EFS was not different between the COPP and COPDAC arms in TG-2 and TG-3. In TG-1, ESR >30 or bulky disease was associated with inferior EFS.33 This trial suggests that RT can be eliminated in patients who are PET-negative after chemotherapy, and dacarbazine can safely replace procarbazine in COPP, therefore only the COPDAC arm is included in the guidelines.33
In the COG AHOD0431 trial, the goal was to evaluate the efficacy of a lower-intensity regimen, AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide), in pediatric and AYA patients (≤21 years of age) with nonbulky, stage IA and IIA CHL.34 All patients (n=278) were treated with 3 cycles of AVPC, and patients who were not in CR after 3 cycles received 21 Gy of IFRT. Patients who experienced a protocol-defined, low-risk relapse after chemotherapy alone were eligible for an integrated salvage regimen composed of vinorelbine, ifosfamide, dexamethasone, etoposide, cisplatin, and cytarabine, with growth factor support for 2 cycles, and IFRT.34 At 4 years, 49.0% of patients had been treated with 3 cycles of AVPC without RT and 88% were in CR without receiving HDT/ASCR or >21 Gy of IFRT. The OS rate was 99.6%. Patients with mixed cellularity histology had a 4-year EFS of 95.2% compared with an EFS of 75.8% in patients with nodular sclerosis histology (P=.008).34 In this study, a negative PET scan after 1 cycle of chemotherapy (PET1) and an ESR rate ≤20 mm/hour were associated with a favorable EFS outcome.34
NCCN Recommendations for Low-Risk CHL
For patients with stage IA, IIA, and IB CHL (with or without bulky disease; no E-lesions), the panel recommends enrollment in an ongoing clinical trial or treatment according to EuroNet-PHL-C1 (a category 1 recommendation) as the preferred strategies (see PHL-3, page 736). In certain circumstances, for patients with mixed cellularity histology, 3 cycles of AVPC may be considered per the AHOD0431 trial.
After initial cycles of chemotherapy, patients with adequate response may avoid RT and move to routine follow up. Patients with inadequate response receive ISRT (to all sites and boost to sites of inadequate response per EuroNet-PHL-C1 [see PHL-A 1 of 2, page 741]). Based on an end of therapy PET assessment, patients may either be followed or consider reinduction therapies if there is a concern for persistent disease.
In some pediatric patients with CHL, the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) may be considered.35–39 The panel recommends referring to the NCCN Guidelines for Hodgkin Lymphoma in adults (available at NCCN.org) to review relevant data and context.
Intermediate-Risk CHL
The phase III COG AHOD0031 study evaluated the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate risk HL.40 Patients with newly diagnosed intermediate risk HL (n=1,712; aged <22 years) received 2 cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone) followed by early response assessment with PET/CT. For patients who experienced adequate response (rapid early response [RER], based on anatomic criteria), 2 additional cycles of ABVE-PC were given followed by response assessment. RERs with CR (80% or greater reduction in the PPD or a return to normal size for all target lesions, plus no residual extramediastinal nodal mass >2.0 cm, no residual disease in nonmeasurable sites, and a negative gallium or FDG-PET scan) were randomly assigned to IFRT (21 Gy) or observation, and RERs with less than CR were nonrandomly assigned to receive IFRT. In patients who experienced inadequate response (slow early response [SER]) after 2 cycles of ABVE-PC, they were randomly assigned to receive or not receive 2 cycles of chemointensification with DECA (dexamethasone, etoposide, cisplatin, and cytarabine) followed by 2 additional cycles of ABVE-PC. All patients in the SER group received IFRT.
The overall 4-year EFS was 85% (86.9% for RERs and 77.4% for SERs; P<.001), and the 4-year OS was 97.8% (98.5% for RERs and 95.3% for SERs; P<.001).40 In RER patients who experienced CR at the end of chemotherapy, there was no significant difference in the 4-year EFS rate between patients who received IFRT versus those who did not receive IFRT (87.9% vs 84.3%, respectively). For SER patients who received either DECA or no DECA, the 4-year EFS was 79.3% vs 75.2%, respectively (P=.11). PET response imaging was not required but was obtained on the majority of patients as part of clinical care. Analysis of these data demonstrated that SER patients with PET positive lesions after 2 cycles had a marginal improvement in EFS on the DECA arm (70.7% vs 54.6%, P=.05). Overall, this study showed that RT can be omitted in RERs with CR at the end of chemotherapy, and that augmenting chemotherapy in SERs with PET-positive disease may be beneficial.40
Other clinical studies evaluating the intermediate risk group (TG-2) include the GPOH-HD-2002 and EuroNET-PHL C1 trials32,33 as described under “Low-Risk CHL” (page 741).
NCCN Recommendations for Intermediate-Risk CHL
For patients with stage IA/IIA CHL (with bulky disease; with or without E-lesions), IB CHL (with or without bulky disease or E-lesions), IIB CHL (no bulky disease; with or without E-lesions), and IIIA CHL, the panel recommends enrollment in an ongoing clinical trial or treatment according to AHOD0031 or EuroNet-PHL-C1 as the preferred strategies (see PHL-4, page 737).
For AHOD0031 regimen, after 2 initial cycles of ABVE-PC, patients with adequate response are treated with 2 additional cycles of ABVE-PC. Based on an end of therapy PET assessment and CR achievement by CT criteria, patients may either be followed, or treated with ISRT to all sites if less than CR. Patients with inadequate response receive 2 additional cycles of ABVE-PC and ISRT (see PHL-A 1 of 2, page 741).
For the regimen based on EuroNet-PHL-C1, after 2 initial cycles of OEPA, patients with adequate response are treated with 2 cycles of COPDAC. Patients with inadequate response are treated with 2 cycles of COPDAC and ISRT (to all sites and boost to sites of inadequate response; see PHL-A 1 of 2, page 741). In both cases, based on an end of therapy PET assessment and CT scan, patients may either be followed or considered for biopsy to confirm persistent active disease.
As recommended for low-risk CHL, the ABVD regimen may be considered for some pediatric patients.35–39 The panel recommends referring to the adult NCCN Guidelines for Hodgkin Lymphoma to review relevant data and context.
High-Risk CHL
In a study by the Pediatric Oncology Group (P9425), the efficacy of ABVE-PC in intermediate or high-risk HL (n=216; age <22 years) was assessed.41 After 3 cycles of ABVE-PC, early response was evaluated and patients with RER based on anatomic criteria received IFRT (21 Gy) and those with SER received 2 additional cycles of ABVE-PC (total of 5 cycles) followed by IFRT. Patients were also randomly assigned to receive or not receive dexrazoxane to evaluate its effect as a protectant from anthracycline-induced cardiac and bleomycin-induced pulmonary toxicity. Of 209 evaluable patients, the 5-year EFS was 84% (84% and 85% for intermediate- and high-risk patients, respectively; P=.87).41 The EFS differed between patients with large mediastinal adenopathy (LMA) versus those without LMA (80% ± 4% vs 91% ± 3%; P=.03). However, use of dexrazoxane did not affect EFS, but may increase risk for acute toxicity, especially typhlitis. The 5-year OS was 95% and did not differ between RER and SER groups.41 Overall, this trial allowed a reduction in alkylator and anthracycline exposure in 63% of patients.
In a later COG study, AHOD0831, the investigators aimed to limit alkylator exposure and decrease radiation volumes in pediatric patients with high-risk HL defined as stage IIIB and IVB (n=165; aged ≤21 years).42 All patients received 2 cycles of ABVE-PC; if they experienced RER, they received an additional 2 cycles of ABVE-PC and IFRT (21 Gy) only to sites of initial bulk. Patients with SER received 2 cycles of ifosfamide and vinorelbine followed by 2 more cycles of ABVE-PC and RT to sites of initial bulk disease and slow-responding sites. According to intent-to-treat analysis, the 4-year second EFS (ie, freedom from second relapse or malignancy) was 91.9% (95% CI, 86.1%–95.3%).42 The 5-year first EFS and OS rates are 79.1% (95% CI, 71.5%–84.8%) and 95% (95% CI, 88.8%–97.8%), respectively. Although the projected target for second EFS was not reached (ie, 95%), the EFS and OS rates were comparable to other trials of high-risk HL.41,43 In the phase III COG AHOD1331 trial, further refinements are being investigated, including substituting bleomycin with brentuximab vedotin, a CD30 antibody-drug conjugate, the results of which are pending.44,45
In the Children’s Cancer Group-59704 study, the efficacy of upfront dose intensification with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine, and prednisone) has been evaluated in pediatric patients with high-risk HL (n=99; age <21 years).43,45 All patients received 4 cycles of BEACOPP, and patients with rapid response received either 4 cycles of COPP/ABV and no IFRT (female patients) or 2 cycles of ABVD followed by IFRT (21 Gy) (male patients).43 Patients who were slow responders received an additional 4 cycles of BEACOPP and IFRT. The 5-year EFS and OS rates were 94% and 97%, respectively.43 Although this regimen is effective at maintaining disease control, it is likely to be associated with increased long-term toxicities.45
NCCN Recommendations for High-Risk CHL
For patients with stage IIB, IIIA, IIIB, and IV CHL, the panel recommends enrollment in an ongoing clinical trial or treatment according to AHOD1331 (based on AHOD0831) or EuroNet-PHL-C1 as the preferred strategies (see PHL-5, page 738). Note, not all patients with IIB disease have historically been treated as high risk. Refer to staging algorithm for IIB treatment options (see PHL-2, page 735).
For AHOD1331 regimen, after 2 initial cycles of ABVE-PC, patients with adequate response (rapidly responding lesions) are treated with 3 additional cycles of ABVE-PC and ISRT to sites of LMA. Patients with inadequate response (slow responding lesions) receive 3 additional cycles of ABVE-PC and ISRT to sites of LMA. The addition of boost is dependent on PET-positive lesions at end of chemotherapy (see PHL-A 1 of 2, page 741).
For treatment based on EuroNet-PHL-C1, after 2 initial cycles of OEPA, patients with adequate response are treated with 4 cycles of COPDAC. Patients with inadequate response are treated with 4 cycles of COPDAC and ISRT to all sites and boost to sites of inadequate response (see PHL-A 1 of 2, page 741). In both cases, based on an end of therapy PET assessment, patients may either be followed up or considered for biopsy to confirm persistent active disease.
In certain circumstances, BEACOPP and ABVD regimens may be considered for some pediatric patients.35–39,43 The panel recommends referring to the adult NCCN Guidelines for Hodgkin Lymphoma (available at NCCN.org) to review relevant data and context. It is worth noting that in the NCCN Guidelines for Hodgkin Lymphoma in adults, regimens with reduced numbers of cycles of BEACOPP have been developed.
Follow-Up After Completion of Treatment
Given the long-term risks of the therapies for HL, including secondary cancers, cardiac toxicity, pulmonary toxicity, thyroid dysfunction, and reproductive issues,46–54 patients should be followed up by an oncologist who is aware of these risks and complications, in coordination with the primary care provider, especially during the first 2 years after treatment (see PHL-6, page 739). The follow-up schedule should be individualized, depending on clinical circumstances such as patient’s age, gender, stage of disease, and initial treatment modality.
The panel recommends an interim history and physical examination every 3 to 4 months for 1 to 2 years, then every 6 to 12 months until year 3, and then annually until 5 years. Recommended laboratory studies include: complete blood count with differential, ESR or C-reactive protein, and a chemistry profile as clinically indicated. If the patient’s neck was treated with RT, thyroid stimulating hormone should be evaluated annually. If patients were exposed to regimens that contain bleomycin or pulmonary RT, or have significant pulmonary involvement, or other clinical concerns, PFTs should be considered. At the end of therapy, an echocardiogram may be considered, with repeat echocardiograms thereafter based on specific risk profile (eg, Children’s Oncology Group Long Term Follow-up Guidelines).
An annual influenza vaccination and other vaccines per the CDC is recommended for all patients (see the COG Survivorship Guidelines55 for more details). In addition, in patients treated with splenic RT, vaccinations should be given before or after RT (ie, pneumococcal, meningococcal, and Haemophilus influenzae type b).
Due to risk of false positives, routine or surveillance PET scans are not recommended. If relapse is suspected (based on imaging, clinical, or pathologic correlations) a PET scan may be recommended. It is acceptable to obtain a CT scan with contrast or MRI of original sites of disease at 3 to 6-month intervals for up to 2 years after completion of therapy if there are any concerns. Although an MRI scan may substitute CT scan for neck, abdomen, and pelvic regions, a diagnostic CT of the chest is required for imaging of the chest. If the previous PET was positive (Deauville 3–5), a PET/CT or PET/MRI scan is recommended to confirm CR at the end of all prescribed therapy including RT. The panel notes that once negative, a repeat PET should not be done unless evaluating suspicious findings on the history and physical examination, CT, or MRI. In addition, to minimize false-positive results, it is important to wait at least 8 to 12 weeks after the end of RT to perform PET assessments.
In general, and in terms of monitoring late effects (≥2 years after completion of systemic therapy), patients should be encouraged to undergo counseling on issues regarding survivorship, long-term treatment effects (eg, secondary cancers, cardiac disease, and issues affecting the thyroid, bone, and reproductive health), health habits, and psychosocial issues. For comprehensive details, see the COG Survivorship Guidelines.55
Relapsed or Refractory CHL
Although the outcomes for pediatric HL are excellent, approximately 10% of patients with early-stage disease and up to 25% of patients with advanced-stage disease experience relapse.8,56,57 For patients with relapsed or refractory disease, treatment options include standard-dose chemotherapy (reinduction therapy), high-dose chemotherapy with ASCR, or novel approaches.56 Reinduction regimens (see PHL-E 2 of 3, page 747) can be divided into 4 major categories.56
- 1) Platinum-based regimens including: DHAP58 (dexamethasone, cytarabine, and cisplatin); EPIC59 (etoposide, prednisolone, ifosfamide, and cisplatin); and, GDP60 (gemcitabine, dexamethasone, and cisplatin). In a study of patients with relapsed/refractory (R/R) HL (n=102; median age, 34 years; range, 21–64 years), the response rate after 2 cycles of DHAP was 89%.58 In a retrospective study of 80 children with relapsed or primary refractory HL, treatment with the EPIC regimen (55% of patients received stem cell transplantation after first relapse following EPIC regimen) resulted in a 5-year OS and progression-free survival from relapse of 75.8% and 59.9%, respectively.59 In a study of patients with R/R HL (n=23; median age, 36 years; range, 19–57 years) the response rate after 2 cycles of GDP was 69.5%.60
- 2) Ifosfamide-/etoposide-based regimens including: ICE61 (ifosfamide, carboplatin, and etoposide); IEP-ABVD62 (ifosfamide, etoposide, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine); IV63 (ifosfamide, and vinorelbine); and a regimen composed of bortezomib and IV.64 The ICE regimen was developed to decrease nonhematologic toxicities observed with cisplatin containing regimens.57,61 In a study of patients with primary refractory or relapsed HL (n=65; median age, 27 years; range, 12–59 years), after treatment with 2 biweekly cycles of ICE, patients who responded to therapy received HDT/ASCR and IFRT. In this study, the response rate to ICE was 88% and the EFS for patients who underwent transplantation was 68%.61
In a study of patients with progressive or relapsed HL (n=167; median age, 14.7 years; range, 4.3–24.5 years), patients were treated with 2 to 3 cycles of IEP alternating with 1 to 2 cycles of ABVD, and supplemented by additional chemotherapy.62 Involved disease sites were also treated with individualized doses of RT. After 10 years, the disease-free survival (DFS) and OS rates were 62% and 75%, respectively.62 This study also identified 3 risk groups, defined as progressive disease on or within 3 months of primary treatment, which had the worst prognosis (DFS/OS rates of 41% and 51%, respectively); early relapse 3–12 months from primary treatment with improved OS (DFS/OS rates of 55% and 78%, respectively); and late relapse more than 12 months from primary treatment. This had significantly better DFS (DFS/OS rates of 86% and 90%, respectively), even though this group did not receive stem cell transplantation in second CR.56,62
In a study evaluating the efficacy of the IV regimen, 66 patients younger than 30 years of age with R/R HL were treated with 2 cycles of IV.63 The overall response rate (ORR) of 72% allowed most of the patients to undergo subsequent stem cell transplantation.63 It is worth noting that this regimen eliminates etoposide, a chemotherapeutic agent associated with secondary malignancy after transplantation.63,65 Addition of bortezomib to the IV regimen does not improve anatomic CR after 2 cycles, but may improve the ORR at the completion of therapy.64
- 3) Gemcitabine-based regimens including GV66 (gemcitabine and vinorelbine); and IGEV67 (ifosfamide, gemcitabine, and vinorelbine). The GV regimen was evaluated in heavily pretreated pediatric patients with R/R HL (n=30; median age, 17.7 years; range, 10.7–29.4 years).66 All patients had received at least 2 prior chemotherapy regimens and 17 patients had undergone prior autologous stem cell transplantation. Overall, 19 of 25 patients had measurable responses for an observed response rate of 76%.66 Patients who had received transplant before GV tended to respond to therapy over patients who had not received transplant.66 In a study of 12 pediatric patients with primary refractory or relapsed HL (age range, 8–16 years), the ORR to IGEV was 100%, with 58% CRs and 42% PRs.67 The 5-year second EFS and OS rates were 83.0% ± 11.0% and 90.0% ± 9.5%, respectively.67
- 4) Targeted therapy and immunotherapy-based regimens include brentuximab vedotin combined with bendamustine,68 gemcitabine,69 or nivolumab70; or single-agent nivolumab71,72 or single-agent pembrolizumab.73,74 In a group of heavily pretreated patients at least 18 years of age with R/R HL (n=64) and anaplastic large cell lymphoma (n=1), the safety and clinical activity of brentuximab vedotin and bendamustine was evaluated.68 An overall response was achieved in 29 of 37 patients (78%).68 In a COG study (AHOD1221), the safety and efficacy of brentuximab vedotin and gemcitabine was evaluated in children and young adults with primary refractory or early relapsed HL (n=46; aged <30 years).69 Of 42 evaluable patients, 24 (57%) had a CR within the first 4 cycles of treatment; 4 of 13 patients (31%) with a PR or stable disease had all target lesions with Deauville scores of ≤2 after 4 cycles of treatment.69 Using a Deauville score threshold of ≤3, 28 of 42 (67%) experienced a CR.
The combination of brentuximab vedotin and nivolumab, a human monoclonal PD-1–directed antibody, has been evaluated as initial salvage therapy in adult patients with R/R HL prior to autologous stem cell transplant (ASCT) with a CR rate of 61% after 4 cycles and no increase in toxicities compared with either agent alone.75 For patients who underwent ASCT after the combination, the 2-year progression-free survival was 91%.76 In a phase II study of children and AYA patients with R/R HL (n=44; median age range, 9–30 years), patients were treated with 4 cycles of brentuximab vedotin and nivolumab experienced complete metabolic response and ORR of 59% and 82%, respectively (according to blinded independent central review).70 No grade 3 or 4 immune mediated adverse events were observed.
Multiple studies have also demonstrated efficacy of nivolumab and pembrolizumab, another human monoclonal PD-1–directed antibody, in adult patients with R/R HL.71–73 In a study evaluating the efficacy of pembrolizumab in pediatric patients with R/R PD-L1-positive solid tumors or lymphomas (n=154 evaluable patients; median age, 13 years; interquartile range, 8–15 years), 9 of 15 patients with R/R HL experienced an objective response (60%).74 In the phase III KEYNOTE-204 study, heavily pretreated adult patients with R/R CHL were randomized to receive either pembrolizumab or brentuximab vedotin (n=300 evaluable patients; pembrolizumab arm, n=148; brentuximab vedotin arm, n=152; aged ≥18 years).77 The median progression-free survival in the pembrolizumab treatment arm was statistically longer than the brentuximab vedotin treatment arm (13.2 vs 8.3 months, respectively; hazard ratio, 0.65; 95% CI, 0.48–0.88; P=.00271).77
Because no randomized trials have been conducted to compare reinduction regimens, none of the regimens are considered to be superior to the other.57 At this stage, desired qualities in a regimen are low toxicity and high efficacy, and other goals of therapy are to obtain cytoreduction/CR before transplant, and to harvest peripheral blood stem cells for ASCT.56
In general, 2 posttransplant treatment options may be considered including: 1) maintenance therapy with brentuximab vedotin (especially useful in patients with high-risk features including progressive disease, refractory disease, or relapse within 1 year of diagnosis)78; and 2) RT consolidation after HDT/ASCR depending on previous receipt of RT. Multiple studies support the addition of RT in the transplant setting by showing benefit for local tumor control and improved EFS/OS/DFS.57,79,80
NCCN Recommendations for Relapsed/Refractory CHL
Histologic confirmation with biopsy is recommended before initiating treatment of relapsed/refractory disease (see PHL-7, page 740). If the biopsy is negative, the panel recommends either observation with short-interval follow-up or additional workup if high index of suspicion for relapse remains. If the biopsy is positive, the panel recommends enrolling the patient in a clinical trial if available, and referral to or consulting with a center of expertise as several options exist for the treatment of relapsed/refractory disease, and lack of data to support one regimen over another.
Typically, patients are treated with reinduction therapies, and after a PET/CT or PET/MRI assessment, if metabolic CR is observed (Deauville score ≤3), treatment can be followed up with HDT/ASCR with or without ISRT and with or without maintenance therapy. In general, RT is performed as consolidation after transplant. If unable to achieve a metabolic CR, RT may be used before transplant.
In certain cases, patients may avoid ASCR. These include patients with initial stages other than IIIB or IVB, patients who have no prior exposure to RT, patients with duration of first CR >1 year, and patients with no extranodal disease or B symptoms at relapse. In these patients, reinduction therapy plus ISRT may be considered for initial treatment of R/R HL.
After initial reinduction therapy, an assessment with PET/CT or PET/MRI is recommended to evaluate response. If PET-negative, patients may be observed with short-interval follow-up. If PET-positive, subsequent therapy options should be considered, including reinduction options that were not previously used.
Summary
Pediatric HL is now curable in most patients because of the introduction of more effective and less toxic regimens. However, survivors may experience late treatment-related side effects. For this reason, long-term follow-up is essential after completion of treatment. In addition, improvements in harmonization of staging and response criteria, and risk stratification will improve the therapeutic index.8 Emerging data will continue to inform the panel’s recommendations and 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. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Pediatric Hodgkin Lymphoma are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2021. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Pediatric Hodgkin Lymphoma Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Pediatric Hodgkin Lymphoma Panel members can be found on page 754. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
