Treatment of relapsed or refractory classic Hodgkin lymphoma

INTRODUCTION — Most patients with classic Hodgkin lymphoma (cHL) attain a complete remission after initial treatment and experience long-term disease control/cure. However, relapse occurs in 10 to 15 percent of patients with favorable prognosis early stage cHL and in 15 to 30 percent of patients with more advanced cHL [1-7]. Approximately 10 to 15 percent of patients have refractory disease that either does not respond to initial therapy or progresses after an initial partial response.

The goal of treatment of relapsed or refractory (r/r) cHL should be to achieve long-term disease control while limiting toxicity and complications of therapy. Salvage chemotherapy can achieve a complete response in more than half of patients with first relapse of cHL or refractory disease, but long-term disease-free survival generally requires autologous hematopoietic cell transplantation (HCT). (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Treatment of r/r cHL with salvage therapy, radiation therapy, and immunotherapy will be reviewed here. The role of HCT in cHL is described separately. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

DEFINITIONS — The following definitions apply for patients with cHL:

●Relapse – Reappearance of disease at sites of prior disease and/or at new sites after achieving a complete response (CR).

●Progression – Progressive disease after achieving a stable partial response (PR).

●Refractory disease – Failure to achieve initial CR or PR; this can be primary (failure to respond to initial therapy) or secondary (initial response but failure to respond after disease relapse).

Progressive disease or relapse usually presents with symptoms related to the enlargement of lymph nodes, liver, or spleen. Progression or relapse are recognized as a 50 percent increase in the longest diameter of a previously identified lesion, appearance of a new site of disease, or new/recurrent involvement of the bone marrow (table 1).

Among patients with relapsed or refractory cHL, approximately one-third each are classified as follows [7,8]:

●Relapsed less than one year after initial CR

●Relapsed more than one year after initial CR

●Refractory disease

CONFIRMING REFRACTORY/RELAPSED DISEASE — It is important to confirm the diagnosis of relapsed cHL, and to determine if apparent residual or progressive disease indeed represents refractory cHL.

Detection of relapsed or refractory disease — Most recurrences of cHL present with symptoms and/or a mass lesion detected on physical examination. As an example, in one study, 81 percent of patients who relapsed were symptomatic; in only four cases was relapse detected as a result of routine physical examination of an asymptomatic patient [8].

After completing initial therapy of cHL, positron emission tomography (PET) is performed to document a complete response (CR), which is defined as PET score 1 to 3 on the five-point (Deauville) score (table 2), according to Lugano criteria [9]. Patients with a CR may have limited residual PET activity due to fibrosis/necrosis that is less than a partial response (PR; ie, PET score 4). Patients with a PET score 4 to 5 should be evaluated by biopsy to document relapsed or refractory cHL.

Biopsy — Diagnosis of relapsed cHL generally requires biopsy of a suspicious mass.

It is sound practice to obtain a tissue diagnosis in most patients with suspected relapsed cHL, but clinical judgment should inform the decision to obtain a biopsy. Other potential sources of PET activity in a suspected late relapse include a second cancer, such as a non-Hodgkin lymphoma or solid tumor, or an inflammatory condition, such as sarcoid-like lesions [10]. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)

A repeat biopsy may not be required for patients with early recurrence in the setting of incomplete response, especially with persistence of constitutional symptoms. However, if the disease was unusually resistant to initial therapy, a biopsy may be warranted to confirm the initial diagnosis of cHL and exclude other diseases.

Staging — Restaging is recommended at the time of relapse, especially if there appears to be an isolated relapse. Restaging is important for assessing prognosis and for guiding treatment, including selection and duration of chemotherapy, use of radiation therapy, and decisions relating to hematopoietic cell transplantation (HCT) and/or immunotherapy.

Various restaging schemes have been proposed for relapsed cHL, but the most straightforward approach employs the criteria of the Ann Arbor staging system with Cotswolds modification to describe the extent of disease at the time of relapse and substitutes the letters RS (relapse stage) for CS (clinical stage) or PS (pathologic stage) (table 3). This is discussed in more detail separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma" and "Classic Hodgkin lymphoma (cHL): Treatment of unfavorable prognosis early (stage I-II) cHL in adults" and "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Monitoring'.)

Prognosis — The effectiveness of salvage therapy for relapsed cHL is associated with clinical characteristics, such as age, stage, symptoms, duration of first remission, anemia, and extent of prior therapy [11-14].

As an example, the German Hodgkin Lymphoma Study Group (GHSG) identified the following adverse risk factors among 422 patients relapsing after primary radiation therapy or chemotherapy [14]:

●Time to recurrence ≤12 months

●Stage III or IV disease at relapse

●Decreased hemoglobin (<10.5 or <12 g/dL in females and males, respectively)

These risk factors were incorporated into a relapsed cHL prognostic score. Actuarial four-year overall survival for patients relapsing after chemotherapy was 83, 66, 36, and 27 percent for those with zero, one, two, or three unfavorable factors, respectively. Subsequent studies by the GHSG confirmed the adverse prognostic value of these risk factors [15,16].

The likelihood of achieving a complete response and a sustained remission diminishes with second and subsequent relapses.

Outcomes following treatment for refractory cHL are even less favorable than following relapse. As an example, an Italian study found that only 8 percent of patients with refractory cHL were alive at eight years [11]. However, among patients who are able to undergo autologous HCT, long-term survival can approach 50 percent [17].

PRINCIPLES OF MANAGEMENT

Overview of management — The goal of treatment of relapsed or refractory (r/r) cHL should be to achieve long-term disease control/cure, while limiting toxicity and complications of therapy [18,19]. In most cases, long-term disease-free survival requires autologous hematopoietic cell transplantation (HCT) [20,21]. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

Patients with first relapse of cHL or refractory cHL are generally treated with intensive combination chemotherapy ("salvage chemotherapy") or targeted chemotherapy (table 4). Those patients with a complete response (CR) upon restaging by positron emission tomography/computed tomographic (PET/CT) proceed to autologous HCT, if eligible (algorithm 1). (See 'Choice of chemotherapy regimen' below and 'Management of first relapse or refractory cHL' below.)

For patients who are not eligible for HCT, treatment decisions must take into consideration the reasons for ineligibility (eg, the type and severity of comorbid illnesses) and the goals of therapy (eg, long-term disease control, palliation of symptoms, prolongation of survival). In this setting, treatment may entail either single agent chemotherapy or combination chemotherapy (as guided by comorbidities), targeted chemotherapy, immunotherapy, and/or radiation therapy (RT). (See 'HCT-ineligible patients' below.)

Patients with a second or subsequent relapse may be candidates for second-line salvage chemotherapy, targeted chemotherapy, immunotherapy, or HCT (if not previously performed). (See 'Second and subsequent relapses' below.)

The therapeutic strategy and sequencing of treatment for r/r cHL is influenced by the following factors:

●Eligibility for HCT (see "Determining eligibility for autologous hematopoietic cell transplantation" and 'HCT-ineligible patients' below)

●Functional response (based on PET/CT examination) to salvage chemotherapy (table 1 and table 3)

●Bulky disease (ie, mediastinal disease greater than one-third of thoracic diameter or mass greater than 10 cm) (see 'Indications for radiation' below)

●Duration of remission (see 'Late first relapse' below)

●Prior therapy, including chemotherapy, targeted chemotherapy, immunotherapy, HCT, and/or RT

●Comorbid illnesses that might limit treatment options

Importance of minimizing disease burden — Long-term survival in the setting of r/r cHL is most likely if a CR is achieved, as defined by a negative PET/CT (table 1 and table 2). However, some patients with a partial response (PR) to salvage chemotherapy can be cured with autologous HCT.

For most patients, salvage chemotherapy should be followed by autologous HCT. Those who achieve a CR proceed directly with HCT.

For patients who achieve PR to salvage therapy, we favor using further salvage chemotherapy, radiation therapy, or targeted chemotherapy (eg, brentuximab vedotin) to minimize disease burden prior to HCT (algorithm 1). (See 'Management of first relapse or refractory cHL' below.)

The importance of achieving a CR prior to transplantation is supported by experience with PET/CT scans obtained after salvage chemotherapy, but prior to autologous HCT. In one series, CR on PET scan had a positive predictive value of 93 percent for progression-free survival (PFS) at two years; in contrast, the majority of PET-positive patients relapsed despite high dose therapy [22].

However, an acceptable option for patients who achieve a PR or lesser response is proceeding directly to autologous HCT rather than treating with a third line of chemotherapy (with or without RT) [23]. It is not clear whether additional therapy prior to autologous HCT improves outcomes. A trial randomly assigned 241 patients with relapsed cHL to salvage therapy with DHAP (dexamethasone, cytarabine, and cisplatin) followed by autologous HCT, versus DHAP followed by sequential salvage chemotherapy (cyclophosphamide, methotrexate, and etoposide) prior to autologous HCT [24]. The more intensive treatment regimen caused greater toxicity, but it did not achieve improved overall survival (OS) or freedom from treatment failure.

Choice of chemotherapy regimen — There is no consensus salvage chemotherapy regimen for r/r cHL, and clinical practice varies widely (table 4). We generally prefer salvage therapy with ICE (ifosfamide, carboplatin, etoposide) for most patients who are candidates for HCT. Our preference for ICE is largely based on a comparable efficacy to other salvage regimens, its favorable toxicity profile compared with some other treatments, and our familiarity with the protocol.

Most patients are treated with two cycles of salvage chemotherapy, with or without RT, followed by autologous HCT [25,26]. Decisions to incorporate RT, alternative salvage chemotherapy, targeted chemotherapy, and/or immunotherapy are addressed in the sections below, and in the algorithm (algorithm 1).

The most common salvage chemotherapy regimens for r/r cHL are:

●ICE (ifosfamide, carboplatin, etoposide) [27-29] – Hematologic toxicity is universal with approximately 35 percent of patients requiring transfusion of blood products. Severe (grade 3/4) nonhematologic side effects include infection (23 percent) and nephrotoxicity (1 percent). Stem cell mobilization appears adequate.

●Gemcitabine-containing regimens – The most common regimens are:

•GVD (gemcitabine, vinorelbine, pegylated liposomal doxorubicin) [30]

•GDP (gemcitabine, dexamethasone, cisplatin) [31]

•BeGEV (bendamustine, gemcitabine, vinorelbine) [32]

Hematologic toxicity is universal with these gemcitabine-containing regimens. Febrile neutropenia is seen in approximately 15 percent of patients. Stem cell mobilization for autologous HCT is generally adequate after these regimens.

●DHAP (dexamethasone, cytarabine, cisplatin) [33] – Hematologic toxicity is universal with more than half of patients requiring transfusion of blood products. Severe (grade 3/4) nonhematologic side effects include infection (24 percent) and nephrotoxicity (6 percent). Stem cell mobilization appears adequate.

●Targeted chemotherapy (eg, brentuximab vedotin [BV] plus bendamustine) – Toxicity includes cytopenias and infections, as described below. (See 'Brentuximab vedotin' below.)

No randomized trials have directly compared various salvage regimens for relapsed cHL. In phase 2 studies, response rates for these regimens generally ranged from 60 to 85 percent, but comparison is difficult since most studies involve small numbers of patients with variable clinical status, and many were subsequently treated with HCT.

Toxicity of these regimens is substantial, and patient comorbidities may influence the selection of a particular chemotherapeutic regimen. Hematologic toxicity is common, and many patients will require antibiotics for fever/infection or transfusion with red blood cells and/or platelets.

The ICE regimen is usually administered in the inpatient setting (or may be given in the outpatient setting for select patients) over three days with a cycle length of 14 or 21 days (as permitted by recovery of blood counts) [28]:

●Ifosfamide 5 g/m² with equivalent dose of MESNA given over 24 hours by continuous infusion on day 2.

●Carboplatin to an area under the curve (AUC) of 5 with a maximum of 800 mg on day 2.

●Etoposide 100 mg/m²/day on days 1 to 3.

●Granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg daily on days 5 to 12.

Dose adjustments may be necessary for pre-existing renal or liver dysfunction. In addition to monitoring for kidney dysfunction, electrolyte abnormalities, and cytopenias, urine dipstick testing is performed to evaluate for hematuria, a potential sign of hemorrhagic cystitis. ICE is moderately emetogenic; antiemetic prophylaxis is indicated.

For cHL that is refractory to salvage therapy with ICE or that relapses after ICE, we generally treat with GVD (algorithm 1). (See 'Second and subsequent relapses' below.)

An acceptable alternative for patients whose disease is refractory to or relapses after ICE is to proceed directly to autologous HCT. (See 'Importance of minimizing disease burden' above.)

For patients with significant comorbid illnesses (eg, those who are considered ineligible for HCT because of comorbidities), we may instead treat with single agent chemotherapy (eg, gemcitabine), targeted chemotherapy, RT (especially if the disease can be encompassed in a radiation port), or immunotherapy with the goal of achieving CR, or to palliate symptoms and extend life. (See 'HCT-ineligible patients' below.)

Hematopoietic cell transplantation (HCT)

Autologous HCT — Autologous HCT should be considered the treatment of choice for most patients with r/r cHL (algorithm 1). (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

Sustained remissions after HCT can be achieved in more than one-half of patients with r/r cHL [34,35]. In contrast, long-term disease-free survival is uncommon following salvage chemotherapy (with or without RT) that is not followed by HCT [11-13,36]; the primary exception is patients who experience a late, asymptomatic, isolated relapse of cHL. (See 'Late first relapse' below.)

Benefits from HCT compared with chemotherapy alone are especially marked in the following categories of patients:

●Early relapse (<12 months after completion of initial therapy)

●Generalized systemic relapse, or the presence of other poor prognostic markers

●Second (or later) relapse

●Refractory cHL (ie, induction failure after initial chemotherapy)

Clinical trials that have compared HCT versus salvage chemotherapy (with or without RT) without HCT include the following:

●In a randomized study from the German Hodgkin Lymphoma Study Group and the European Group for Blood and Marrow Transplantation, 161 patients with relapsed cHL were treated with two cycles of chemotherapy (dexa-BEAM: dexamethasone, carmustine, etoposide, cytarabine, melphalan) [37]. Those with chemosensitive disease were treated with either high dose BEAM followed by autologous HCT or two additional courses of dexa-BEAM without subsequent HCT. At a median follow-up of 39 months:

•OS was similar in the two treatment arms.

•Freedom from treatment failure at three years favored HCT over chemotherapy alone (55 versus 34 percent, respectively).

●A prospective, nonrandomized GELA (Groupe d'Etude des Lymphomes de l'Adulte) trial enrolled 157 patients with stage IIIB or IV cHL who had refractory disease, PR, or early relapse following initial chemotherapy [38]. Patients were treated with MINE (mesna, ifosfamide, mitoxantrone, etoposide) salvage chemotherapy, with or without subsequent autologous HCT. At a median follow-up of 50 months, the following observations were made:

•Five-year estimated OS rates were 71 and 32 percent for patients undergoing HCT or not undergoing autologous HCT, respectively.

•Salvage chemotherapy without HCT was an independent predictor of poor OS in multivariate analysis; "B" symptoms at the time of disease progression and refractory disease before HCT were also associated with shorter OS.

Allogeneic HCT — Allogeneic HCT may be offered to patients with cHL as a salvage therapy following relapse or progression after autologous HCT. The use of allogeneic HCT in this setting is discussed in more detail separately. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma" and "Hematopoietic cell transplantation in classic Hodgkin lymphoma", section on 'Allogeneic transplantation'.)

Caution should be exercised in considering allogeneic HCT in patients who previously received a PD-1 inhibitor (nivolumab or pembrolizumab) because of reports of increased toxicity, as discussed below. (See 'GVHD with PD-1 blockade and allogeneic HCT' below.)

Targeted chemotherapy and immunotherapy — The antibody-drug conjugate, brentuximab vedotin, preferentially delivers chemotherapy to CD30-expressing cells, including the Hodgkin Reed-Sternberg cells of cHL. Immunotherapy approaches include strategies to overcome evasion of immune surveillance (ie, immune checkpoint blockade) and can achieve high rates of response in r/r cHL. It remains unclear if such treatments can achieve long-term remissions and obviate the need for subsequent HCT.

Brentuximab vedotin — Brentuximab vedotin (BV) is an antibody-drug conjugate that comprises an anti-CD30 antibody linked to the anti-tubulin agent, monomethyl auristatin E [39]. In the United States and Europe, BV is approved for the treatment of patients with cHL after failure of autologous HCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for HCT. A subset of patients achieved sustained, unmaintained remissions, even in the absence of transplantation [40], while others were able to proceed with reduced intensity allogeneic HCT [41]. Use of BV in patients who have already completed autologous HCT is presented in more detail separately. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma", section on 'Maintenance therapy'.)

A meta-analysis of six studies (302 patients) reported 61 percent overall response (OR) and 38 percent CR to single agent BV [42]. BV is also effective when combined with other chemotherapy agents (eg, BV plus bendamustine) [43,44].

Informative studies include:

●A multicenter phase II study reported 75 percent OR (34 percent CR) among 102 patients with r/r cHL following autologous HCT who received BV (1.8 mg/kg every three weeks for up to 16 cycles) [40,45,46]. For the 34 patients who achieved CR, estimated five-year OS and PFS rates were 64 and 52 percent, respectively. Thirteen of these patients (38 percent of patients who achieved CR) remained in remission at the close of study, including nine who remained in sustained remission without any further anticancer therapy or allogeneic HCT.

●Two phase I/II studies that treated patients with r/r cHL with BV plus bendamustine reported high rates of OR (93 and 78 percent) and CR (74 and 43 percent) [43,44].

Infusion reactions with BV are uncommon, but the rates of reactions are higher when BV is given in combination with bendamustine; this can be mitigated by pretreatment steroids and antihistamines on each day of therapy. Anaphylaxis to BV has been reported, and infections, cytopenias, gastrointestinal complications (eg, hemorrhage, perforation, obstruction), and other adverse effects have been reported [47]. Progressive multifocal leukoencephalopathy and acute pancreatitis are rare complications of brentuximab treatment [48-50]. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Brentuximab' and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

PD-1 blockade

Efficacy — Programmed death 1 (PD-1) ligands, PD-L1 and PD-L2, are overexpressed by Hodgkin Reed-Sternberg cells in cHL, leading to evasion of immune surveillance. Small prospective studies have reported high response rates with PD-1 inhibitors (eg, nivolumab, pembrolizumab), but further study is required to characterize the durability of treatment.

In the United States and Europe, nivolumab is approved for patients with cHL that relapsed or progressed after autologous HCT and post-transplantation brentuximab vedotin (BV). Pembrolizumab is approved in the United States for patients whose disease is refractory or has relapsed after two or more lines of therapy, and in the European Union for patients with progression after autologous HCT and BV, or who are transplant-ineligible and have failed BV. Pembrolizumab is approved for administration as 400 mg every six weeks or 200 mg every three weeks by the US Food and Drug Administration [51].

Adverse events reported with anti-PD-1 monoclonal antibodies include pneumonitis, colitis, hepatitis, thyroid dysfunction, nephritis, and renal dysfunction. Rash, pruritus, fatigue, fever, nausea, diarrhea, and metabolic abnormalities (eg, hypophosphatemia, hypercalcemia, and increased lipase levels) are also frequent but generally mild (grade 1/2). Toxicity associated with these agents is discussed separately. (See "Toxicities associated with immune checkpoint inhibitors".)

Support for anti-PD-1 monoclonal antibody therapy in this setting comes from several prospective trials of heavily pretreated patients:

●A multicenter phase 2 trial of nivolumab reported OR and CR rates of 69 and 16 percent, respectively, among 243 patients with r/r cHL, of whom 180 had previously received BV and autologous HCT [52]. Median duration of response and median PFS were 17 and 15 months, respectively.

●A phase 2 study of nivolumab in 80 adults with r/r cHL after autologous HCT and/or BV reported a 66 percent OR rate (9 percent CR), with a median duration of response of 7.8 months [53].

●The phase II KEYNOTE-087 study reported that pembrolizumab 200 mg every three weeks was effective for BV-naïve patients and for those treated with BV before or after HCT [54]. The study reported 72 percent OR, including 28 percent CR, in 210 heavily pretreated patients with r/r cHL. For two-thirds of patients who achieved CR, at least one year of treatment was required. Responses were durable, with 14 month median PFS; two-year PFS was >60 percent among patients who achieved CR. Grade ≥3 treatment-related toxicity was reported in 11 percent, and none led to death; compared with an earlier report of this study, no unexpected toxicity was noted with more than two years of follow-up [55]. For 19 patients treated with a second course of pembrolizumab for subsequent relapse, OR was 71 percent, including 28 percent CR; one-half of patients with CR maintained a response for ≥4 years [56].

Use of PD-1 blockade as maintenance therapy after autologous HCT for r/r cHL is discussed separately. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma", section on 'PD-1 blockade maintenance'.)

GVHD with PD-1 blockade and allogeneic HCT — Patients treated with nivolumab or pembrolizumab who proceed to allogeneic HCT have an increased rate of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic sinusoidal obstruction syndrome, and other immune-related adverse reactions. Conversely, there are reports of acute GVHD developing with nivolumab treatment in patients who had previously undergone allogeneic HCT. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Combining or sequencing immunotherapy with other therapies'.)

Acute GVHD developed in 6 of 20 (30 percent) who were treated with nivolumab after having previously relapsed following allogeneic HCT; GVHD began within one week after the first infusion of nivolumab [57]. All six patients had a prior history of acute GVHD. Two patients died as a result of GVHD; one died with progressive disease, and one died with complications related to a second allogeneic HCT. The OR to nivolumab was 95 percent and median PFS was not reached after more than one year of observation. Another retrospective study reported outcomes in 39 patients with hematologic malignancies who were treated with a PD-1 inhibitor and subsequently underwent allogeneic HCT (all but three with reduced intensity conditioning) [58]. There were more complications (four treatment-related deaths; one from hepatic sinusoidal obstruction syndrome, three from early acute GVHD), and seven patients developed a noninfectious febrile syndrome that required treatment with steroids. Additional studies in larger groups of patients are needed to determine whether prior treatment with a PD-1 inhibitor increases the toxicities of allogeneic HCT.

CAR-T cell therapy — Autologous T cells that bear a chimeric antigen receptor (CAR) targeted against CD30 can achieve a high rate of durable responses in patients treated with lymphodepleting conditioning therapy, with only modest toxicity.

Anti-CD30 CAR-T cells (from 2 x 10⁷ to 2 x 10⁸ cells/m²) were administered to 32 heavily-pretreated, evaluable patients after treatment with one of three different lymphodepleting preconditioning regimens [59]. The overall response rate was 72 percent (including 59 percent CR) and, with median follow-up of nearly 1.5 years, one-year PFS was 36 percent, and one-year OS was 94 percent. Neutropenia or thrombocytopenia that did not resolve by day 28 were reported in 10 and 24 percent of patients, respectively. Cytokine release syndrome (CRS) was reported in 24 percent, but all were grade 1; no neurologic toxicity was observed. In an earlier study, administration of CAR-T cells that did not include lymphodepleting preconditioning therapy was associated with only limited activity (33 percent overall response rate) [60].

Radiation therapy (RT)

Indications for radiation — The decision to offer RT must balance the potential improvement of local disease control against the potential for long-term toxicity, including second malignancies and cardiovascular morbidity. Our decision to offer RT depends on the following clinical factors (algorithm 1):

●For patients undergoing autologous HCT – We offer RT to achieve CR prior to HCT or to consolidate the CR in patients who had bulky disease at the time of relapse, as follows:

•Consolidative RT may be administered prior to transplantation for patients who had a PR (by PET/CT) to salvage chemotherapy with residual disease that can be encompassed in a radiation port.

•Consolidative RT may be used after autologous HCT for patients who had bulky disease at the time of relapse and for select patients with non-bulky disease that can be encompassed in a radiation field.

There are no randomized trials indicating a survival benefit, but several studies have shown that adjuvant irradiation can control limited residual disease and may contribute to improved prognosis. This is discussed separately. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma", section on 'Radiation of localized or bulky disease'.)

●Late first relapse – Salvage chemotherapy followed by RT may be an option for select patients with a late (generally at least several years after completion of initial treatment), localized, asymptomatic, first recurrence of cHL. (See 'Late first relapse' below.)

●Palliation without curative intent – RT, with or without systemic chemotherapy or targeted chemotherapy, may provide relief of symptoms in select patients who are not able to undergo chemotherapy and/or HCT with curative intent.

Can radiation be given alone? — In general, long-term control of r/r cHL requires systemic chemotherapy, with or without RT, followed by HCT (except as described above). (See 'Overview of management' above.)

RT is rarely used as the only salvage treatment for relapsed cHL. There are some reports of success in highly selected patients with favorable prognostic criteria (eg, long disease-free intervals, absence of extranodal sites, and no B symptoms) whose disease can be encompassed in a reasonable radiation port [61-63].

A retrospective analysis of 100 patients who received salvage RT reported a 77 percent CR rate for the 80 patients who received either mantle or involved field RT, but the five-year freedom from progression (FFP) rate was only 28 percent [64]. This low FFP rate indicates that RT salvage alone is not generally sufficient for long-term disease control.

SPECIFIC CLINICAL SCENARIOS

Management of first relapse or refractory cHL — A guiding principle for our approach to managing first relapse of cHL or refractory disease is to attempt to achieve a complete response (CR) and then proceed to autologous hematopoietic cell transplantation (HCT). In some cases, achieving CR may entail the sequential use of systemic chemotherapy, radiation therapy (RT), targeted chemotherapy, or immunotherapy to achieve CR prior to HCT (algorithm 1).

Management of HCT-ineligible patients is described below. (See 'HCT-ineligible patients' below.)

Salvage chemotherapy (often with RT) is an acceptable alternative to HCT in select patients with a late (generally at least several years after completion of initial treatment), localized (ie, single site of relapse), asymptomatic, first relapse of cHL. (See 'Late first relapse' below.)

We initially treat relapsed or refractory cHL with two cycles of salvage therapy with ICE (ifosfamide, carboplatin, etoposide). Alternative regimens for initial salvage chemotherapy may be selected based on the presence of comorbid illnesses, toxicities, and other clinical features. (See 'Choice of chemotherapy regimen' above.)

Three weeks after completion of salvage therapy with ICE, we perform a positron emission tomography/computed tomographic (PET/CT) examination to determine response (algorithm 1 and table 1).

Subsequent therapy is guided by PET/CT results, as follows:

●CR – PET (Deauville) score 1 to 3:

HCT-eligible patients should proceed to autologous HCT. (See "Determining eligibility for autologous hematopoietic cell transplantation" and "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

Those who had bulky disease at the time of relapse, or localized disease that was not previously irradiated, may receive involved-site RT consolidation after HCT. (See 'Indications for radiation' above.)

These patients should be evaluated for brentuximab vedotin maintenance therapy after HCT. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma", section on 'Maintenance therapy'.)

●Partial response (PR) – PET (Deauville) score 4 or 5:

For patients with residual disease after two cycles of ICE, we generally treat with two cycles of second-line salvage chemotherapy (eg, GVD [gemcitabine, vinorelbine, pegylated liposomal doxorubicin] or other alternative salvage regimens) (see 'Choice of chemotherapy regimen' above). Other experts offer HCT to select patients at this time rather than proceeding with further chemotherapy [23].

PET/CT is performed three weeks later, and management is guided by the results, as follows:

•CR (PET score 1 to 3) – HCT-eligible patients should proceed to autologous HCT.

•PR (PET score 4 or 5) or progressive disease – Disease that can be encompassed in a radiation port is treated with involved-site RT. PET/CT is repeated three weeks after completion of RT. We proceed to HCT if there is no evidence of progression outside of the radiation field; note that PET/CT may demonstrate persistent inflammation-related activity within the radiation field. (See 'Radiation therapy (RT)' above.)

For disease that cannot be encompassed in a radiation port, we treat with alternative salvage chemotherapy (eg, DHAP [dexamethasone, cytarabine, cisplatin]), targeted chemotherapy (eg, brentuximab vedotin), or immunotherapy (eg, PD-1 blockade). (See 'Choice of chemotherapy regimen' above and 'Targeted chemotherapy and immunotherapy' above.)

-For patients who achieve CR by PET/CT after completing this therapy, we proceed to HCT.

-For patients who achieve PR after completing this therapy, we treat with involved-site RT (if disease can be encompassed in a radiation field) prior to HCT.

-For patients with PD, we treat with RT (if appropriate) and may offer targeted chemotherapy, immunotherapy, or HCT, if the patient is eligible for these treatments; if not, we focus on palliation of symptoms.

●Progressive disease (PD) – We treat with serial systemic therapies aimed at achieving CR. Acceptable options include alternative salvage chemotherapy (single agent or combination), targeted chemotherapy, immunotherapy, proceeding to autologous HCT, or participation in a clinical trial.

For some patients, the goal of relieving symptoms or palliative care may be the proper course of action. (See 'Clinical trials' below.)

HCT-ineligible patients — Patients who are ineligible for HCT because of comorbid illnesses or advanced age (the age of eligibility for HCT is usually determined by treating institution) are treated with the goal of achieving CR and long-term disease control. In some cases, the goal may simply be symptom relief. Selection of systemic treatment may be influenced by likelihood of tolerance of salvage therapy. As examples, we usually offer brentuximab vedotin or single agent gemcitabine, rather than intensive combination chemotherapy, such as ICE. Serial administration of single agent chemotherapy regimens may offer benefit with tolerable toxicity. (See 'Second and subsequent relapses' below.)

This may be followed by RT, if appropriate, with the goal of achieving CR.

Following completion of therapy, we observe patients with follow-up visits every three months for the first two years, and every six months thereafter. Follow-up visits include history and physical examination to monitor for recurrence of disease or side effects of therapy, and laboratory studies (eg, complete blood count with differential, erythrocyte sedimentation rate [ESR], and chemistry studies, including electrolytes, kidney function, and liver function tests). We do not perform routine surveillance PET/CT following CR.

Late first relapse — Salvage chemotherapy (often with RT) is an acceptable alternative to HCT in select patients with a late (generally at least several years after completion of initial treatment), localized (ie, single site of relapse), asymptomatic, first relapse of cHL. In this setting, treatment with conventional dose chemotherapy, with or without RT, can achieve long-term survival in 50 to 80 percent of patients, even without subsequent HCT [11,65-67]. However, a majority of such patients may achieve long-term lymphoma-free survival after autologous HCT in this setting [68].

In this setting, we offer two to three cycles of salvage chemotherapy (eg, ICE) followed by consolidative RT to the site of relapse. (See 'Choice of chemotherapy regimen' above.)

Risks and benefits of consolidation with autologous HCT should be discussed with the young fit patient who achieves CR in this setting. (See 'Autologous HCT' above.)

Rarely, such a patient may have received initial induction therapy with a regimen that did not include an anthracycline (eg, MOPP). If so, that patient may be considered for treatment with four to six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or another first-line regimen that was not used initially, with or without RT (table 5) [11,36,69,70].

A decision to forego HCT in this setting must weigh the toxicity of cumulative doses of chemotherapy (both prior and planned therapy) and should specifically consider possible cardiac toxicity from anthracycline therapy and radiation, pulmonary toxicity from bleomycin, and neurotoxicity from vinca alkaloids.

Second and subsequent relapses — Special consideration must be given to patients in the setting of second or subsequent relapse of cHL. Such individuals will have already received at least one form of salvage chemotherapy, targeted chemotherapy, radiation therapy, immunotherapy, and/or HCT. The likelihood of achieving a sustained complete remission diminishes with additional relapses. In this setting, toxicities associated with prior therapy, comorbidities, and other considerations will inform the therapeutic strategy.

Options for treatment are influenced by the number of prior relapses, the nature of prior treatments (eg, initial and salvage chemotherapy regimens, prior autologous and/or allogeneic HCT, immunotherapy), and the individual's general medical condition and goals of treatment (ie, treatment with curative intent versus relief of symptoms).

Therapeutic options include:

●Further salvage chemotherapy, which must consider residual and/or likely toxicities from prior treatment (eg, cardiotoxicity from anthracyclines, nephrotoxicity and/or neuropathy from platinum-containing regimens).

●Targeted chemotherapy (eg, brentuximab vedotin).

●Immunotherapy approaches (eg, PD-1 blockade).

●Autologous HCT, if not previously performed (or reduced intensity allogeneic HCT, if the patient previously underwent autologous HCT). (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

●Sequential administration of targeted chemotherapy, immunotherapy, and single agent chemotherapy (eg, gemcitabine, etoposide, vinorelbine, vinblastine, liposomal doxorubicin, bendamustine) may offer palliation of symptoms with relatively low toxicity.

●Participation in clinical trials.

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

Many agents are under active investigation or in development for relapsed or refractory cHL. Examples include combinations of agents already used in cHL, agents studied in other diseases (eg, rituximab [71,72], ibrutinib [73], everolimus [74], lenalidomide [75], bendamustine [76,77], histone deacetylase inhibitors [78]), novel monoclonal antibodies [79], and other novel agents.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Autologous bone marrow transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Contemporary treatment of classic Hodgkin lymphoma (cHL) cures more than three-quarters of patients, but some patients experience (see 'Definitions' above):

•Relapse – Recurrence after achieving complete response (CR)

•Refractory disease – Failure to achieve an initial CR or partial response (PR)

●Confirm relapsed/refractory (r/r) cHL

•Detection – Most cases present with symptoms and/or a mass detected on physical examination. (See 'Detection of relapsed or refractory disease' above.)

•Confirmation – Biopsy is generally required. For suspected refractory disease, biopsy ensures that the original diagnosis of cHL was correct, and for relapse, it excludes other diagnoses such as a secondary cancer. (See 'Biopsy' above.)

•Staging – Restage prior to treatment with clinical evaluation and positron emission tomography (PET)/computed tomography (CT) using five-point (Deauville) PET score (table 2), per Lugano criteria (table 3). (See 'Staging' above.)

•Prognosis – Inferior features of relapse include <12 months since CR, stage II/IV at relapse, decreased hemoglobin. Refractory disease has worse prognosis than relapse. (See 'Prognosis' above.)

●Overview – The goal of care is long-term disease control/cure, while limiting treatment toxicity and complications. Standard management for medically fit patients is treatment with salvage therapy to minimize disease, followed by autologous hematopoietic cell transplantation (HCT). (See 'Overview of management' above.)

Selected patients with asymptomatic, solitary, late relapse (eg, >2 years since CR) may be considered for RT rather than salvage therapy and autologous HCT. (See 'Late first relapse' above.)

●Salvage therapy – No salvage regimen has been proven superior; selection is individualized by toxicity and comorbidities. Examples of salvage regimens include (see 'Choice of chemotherapy regimen' above):

•ICE – Ifosfamide, carboplatin, etoposide

•Gemcitabine-containing regimens:

-GVD – Gemcitabine, vinorelbine, pegylated liposomal doxorubicin

-GDP – Gemcitabine, dexamethasone, cisplatin

-BeGEV – Bendamustine, gemcitabine, vinorelbine

•DHAP – Dexamethasone, cytarabine, cisplatin

•Immunotherapy-based – Examples include brentuximab vedotin plus bendamustine; nivolumab; pembrolizumab

●Restaging – PET/CT is repeated after salvage therapy. (See 'Importance of minimizing disease burden' above.)

Subsequent management is guided by findings from PET/CT after salvage chemotherapy:

•CR – Patients who achieve CR proceed to autologous HCT, as discussed separately. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

•PR – For patients with a PR, we suggest further therapy to minimize disease burden prior to HCT rather than proceeding directly with HCT (Grade 2C):

-For residual disease that can be encompassed in a single radiation port, we treat with RT prior to HCT. (See 'Indications for radiation' above.)

-For residual disease that cannot be encompassed in a radiation port, we offer alternative salvage chemotherapy, targeted chemotherapy, or immunotherapy. (See 'Choice of chemotherapy regimen' above.)

•Progressive disease (PD) – For PD, we offer sequential salvage therapies; if CR is achieved, we proceed to CR; for others, the goal is palliation of symptoms and prolongation of life.

●Relapse after autologous HCT – We encourage enrollment in a clinical trial.

Management is individualized according to disease tempo, prior therapy, comorbidities, treatment toxicities, and patient/clinician preference. Options include brentuximab vedotin, immune checkpoint inhibitors (eg, nivolumab, pembrolizumab), and allogeneic HCT. (See 'Second and subsequent relapses' above.)

●Patients medically ineligible for transplantation – Management to palliate symptoms and prolong survival is individualized. Lower-intensity treatments include brentuximab vedotin, single agent gemcitabine, or immunotherapy, with or without RT. (See 'HCT-ineligible patients' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter M Mauch, MD, who contributed to earlier versions of this topic review.