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Treatment of nodular lymphocyte-predominant Hodgkin lymphoma

Treatment of nodular lymphocyte-predominant Hodgkin lymphoma
Literature review current through: Sep 2023.
This topic last updated: Aug 02, 2023.

INTRODUCTION — Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinctive, uncommon, and generally indolent subtype of Hodgkin lymphoma (HL). NLPHL has characteristic pathologic features, natural history, and management that distinguish it from all other categories of HL, which are collectively referred to as classic HL (cHL).

NLPHL is the label used by the World Health Organization 5th edition (WHO5) [1], but it is called nodular lymphocyte-predominant B cell lymphoma (NLPBL) by the International Consensus Classification (ICC) [2].

Treatment and prognosis of NLPHL are reviewed here.

Clinical presentation and diagnosis of NLPHL are discussed separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

Evaluation, diagnosis, and treatment of cHL are discussed separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

STAGING AND PRETREATMENT EVALUATION — Staging of NLPHL is based on the Lugano criteria (table 1) [3,4]. Diagnosis and staging of NLPHL are described separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

Pretreatment evaluation of the patient with NLPHL is similar to that of a patient with classic Hodgkin lymphoma (cHL) and is described separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Evaluation'.)

Treatment stratification for NLPHL is based on disease stage and certain prognostic factors; for patients with NLPHL, we do not apply the International Prognostic Score, which is only used for cHL. (See 'Treatment stratification' below.)

TREATMENT STRATIFICATION

Overview of treatment — Selection of treatment must recognize the generally good prognosis of NLPHL at any stage of presentation, so management must seek to limit the risk for acute and long-term toxicity, whenever possible. (See 'Prognosis' below.)

In general, treatment of NLPHL has become less aggressive over time in order to reduce second cancers, cardiac toxicity, and other treatment-related complications while retaining effective and sustained responses. Management trends have focused on limiting radiation, adding anti-CD20 immunotherapy to chemotherapy, and judicious use of active surveillance (AS) as an alternative to immediate treatment.

Treatment of NLPHL should be stratified according to disease stage, based on the Lugano classification (table 1), and certain prognostic factors, as follows:

Non-bulky early stage NLPHL – Patients with non-bulky (ie, <10 cm) stage IA disease or non-bulky, contiguous stage IIA disease who have no significant disease-related symptoms and no mass lesions that threaten organ compromise (eg, compression of the airway or ureters). (See 'Non-bulky early stage NLPHL' below.)

Bulky or non-contiguous early stage NLPHL – Other patients with stage I or stage II NLPHL (ie, ≥10 cm mass, non-contiguous disease, disease-related symptoms, or organ-threatening mass). (See 'Bulky or non-contiguous early stage NLPHL' below.)

Advanced NLPHL – Stage III or stage IV NLPHL. (See 'Advanced NLPHL' below.)

No randomized trials for management of NLPHL have been performed. Outcomes data are derived from single-arm studies, subgroup analysis of Hodgkin lymphoma trials, and retrospective series. Our suggestions are consistent with management approaches of the National Comprehensive Cancer Network (NCCN), the International Radiation Oncology Group (ILROG), and other organizations [5,6]. (See 'Society guideline links' below.)

Non-bulky early stage NLPHL — Non-bulky early stage disease is the largest prognostic category and accounts for more than half of patients with NLPHL [7,8]. Criteria for this favorable category are described above. (See 'Overview of treatment' above.)

There is no consensus regarding optimal management in this setting. For patients with non-bulky early stage disease, we suggest involved-site radiation therapy (ISRT) or AS for selected patients, rather than chemoimmunotherapy or chemoimmunotherapy plus ISRT (combined modality therapy; CMT). ISRT can achieve long-term disease control with modest toxicity. Some patients will instead favor AS to avoid the cost, inconvenience, and potential acute and long-term toxicity of ISRT, but the patient should be committed to long-term follow-up and psychologically comfortable with deferring treatment. We consider the toxicity of chemoimmunotherapy or CMT to be excessive for non-bulky early stage NLPHL.

There are no randomized trials of management in this setting, and our suggestions for management are derived from results from retrospective studies that are described below. (See 'Active surveillance' below and 'Radiation therapy' below.)

Bulky or non-contiguous early stage NLPHL — Bulky or non-contiguous early stage NLPHL includes all patients with stage I or stage II disease who do not meet the criteria for non-bulky disease, as described above. This category accounts for approximately one-quarter of patients with NLPHL [7,8]. (See 'Overview of treatment' above.)

For the rare patient with NLPHL who has B symptoms (ie, fever, drenching sweats, weight loss), we suggest a repeat biopsy to exclude the possibility of transformation or misclassification. (See 'Importance of re-biopsy' below.)

There is no consensus regarding optimal therapy, but for most patients we suggest either chemoimmunotherapy or ISRT (for patients whose distribution of disease is amenable) rather than CMT. We consider that either chemoimmunotherapy or ISRT offers a favorable balance of treatment-free remission with acceptable levels of toxicity; in contrast, we judge that the increased toxicity of CMT is not warranted in this setting. Single-agent rituximab or AS is acceptable for patients who cannot tolerate or do not want more aggressive treatments and for some patients with modest or no symptoms who place greater value on avoidance of toxicity than on the burden of their symptoms.

The choice of approach is guided by the features of the disease, comorbid illnesses, and patient preference. As an example, for a patient with hypertension, diabetes, and a single retroperitoneal mass that risks ureteral obstruction, we might favor ISRT to achieve a rapid response while avoiding potential cardiac events or infectious complications of chemoimmunotherapy. In contrast, for a patient with a non-contiguous, non-bulky stage IIB NLPHL with drenching sweats we might favor chemoimmunotherapy to control the systemic symptoms and avoid multiple sites for radiation. Single-agent rituximab or AS might be preferred for more frail patients or those with modest or no symptoms; however, for patients with NLPHL that involves the spleen, we generally avoid single-agent rituximab because of a possible association with transformation to a more aggressive histology. (See 'Transformation' below.)

No randomized trials have directly compared management approaches, but retrospective studies indicate comparable long-term survival with any of these approaches. Treatment and outcomes with chemoimmunotherapy, radiation therapy (RT), CMT, and AS are described in the sections below. (See 'Chemoimmunotherapy' below and 'Combined modality therapy' below and 'Radiation therapy' below and 'Rituximab' below and 'Active surveillance' below.)

Advanced NLPHL — Advanced NLPHL comprises patients with stages III and IV disease (ie, involvement of both sides of the diaphragm, diffuse, or extranodal disease). Advanced disease accounts for less than one-quarter of patients with NLPHL [7,8].

For patients with advanced NLPHL, there is a broad range of management options, and treatment should be guided by the severity of symptoms:

Symptomatic – For patients with a substantial burden of symptoms, we suggest treatment with chemoimmunotherapy rather than ISRT or CMT. For symptomatic patients with advanced NLPHL, we judge that chemoimmunotherapy provides the most favorable balance of toxicity and disease control and offers the possibility of sustained treatment-free remission. Most advanced disease (ie, above and below the diaphragm) is not amenable to ISRT alone and we consider that CMT is associated with excessive short-term and/or long-term toxicity without a demonstrated benefit. (See 'Chemoimmunotherapy' below.)

For symptomatic patients who do not want or cannot tolerate more aggressive treatments, either single-agent rituximab or rituximab plus ISRT to locally symptomatic disease is acceptable. (See 'Rituximab' below and 'Radiation therapy' below.)

Asymptomatic or minimally symptomatic – For patients with modest or no symptoms and no organ-threatening masses, we consider chemoimmunotherapy, single-agent rituximab, or AS to be acceptable options; selection of the approach should be individualized to reflect patient preferences and concerns. CMT and RT alone do not offer a favorable balance of toxicity versus benefit for minimally symptomatic patients. Some experts avoid treatment with rituximab alone for patients with splenic involvement because of a possible association with transformation to more aggressive histology. (See 'Chemoimmunotherapy' below and 'Rituximab' below and 'Active surveillance' below.)

No randomized studies have directly compared management approaches for advanced disease. Retrospective studies indicate that all of these approaches achieve comparable long-term survival, so the choice of approach is primarily informed by the nature and severity of symptoms, a need for a prompt response to treatment, comorbid illnesses, and short-term and long-term toxicity.

Treatment approaches and outcomes are described in the sections below. (See 'Combined modality therapy' below and 'Chemoimmunotherapy' below.)

MANAGEMENT

Active surveillance — Active surveillance (AS) refers to close monitoring of a patient without specific treatment at the time of diagnosis. AS is an acceptable option for patients who have no residual disease following the diagnostic biopsy and for selected asymptomatic patients who have clinically detectable disease.

AS is an acceptable approach for the patient who has modest or no symptoms from the lymphoma, no organ-threatening masses, is psychologically comfortable with deferring treatment, and is reliable and committed to long-term follow-up. AS offers the advantages of avoiding the cost, inconvenience, and potential acute and long-term toxicity of chemoimmunotherapy and/or radiation therapy (RT), but it may cause unacceptable anxiety due to awareness of the presence of a treatable malignancy. AS is particularly advantageous for children, because treatment may cause growth retardation, infertility, hypothyroidism, cardiopulmonary complications, or secondary malignancy [9-12]. (See "Overview of Hodgkin lymphoma in children and adolescents", section on 'Late complications'.)

There is no need for routine imaging of the patient undergoing AS; other aspects of monitoring are described below. (See 'Monitoring' below.)

No randomized studies have directly compared AS with treatment for NLPHL, but retrospective studies indicate that AS is associated with comparable long-term survival with less toxicity. In general, one-quarter to one-half of patients on AS will have progressive disease or relapse, but there is no evidence that the disease is less responsive or that treatment at the time of relapse is associated with inferior outcomes. For progressive or relapsed disease during AS, we suggest a repeat biopsy to determine if it represents transformation to a more aggressive histology. (See 'Relapsed/refractory disease' below.)

Studies that included AS include:

A single institution study of 163 consecutive patients ≥16 years old with newly diagnosed NLPHL reported that outcomes with AS (23 percent of patients) were equivalent to outcomes with RT alone (46 percent), systemic chemotherapy alone (16 percent), combined modality therapy (CMT; 12 percent), and single-agent rituximab (4 percent) [13]. Most patients in this series were male (63 percent), had stage I or II disease (74 percent), and were asymptomatic (96 percent). Extranodal or mediastinal involvement was present in 7 and 14 percent, respectively.

With median follow-up of 69 months (range, 4 to 512 months), overall survival (OS) for the entire study cohort was 99 percent, and only one patient died from progressive lymphoma [13]. Compared with patients who underwent treatment at the time of diagnosis, AS was associated with shorter progression-free survival (PFS); five-year PFS for AS was 77 percent (95% CI 56-89 percent) versus 87 percent (95% CI 79-92 percent) for patients who received treatment. However, there was no disadvantage for AS with regard to OS, long-term disease control, or responsiveness to subsequent treatment. Among the 37 patients on AS (23 early stage, 14 advanced stage disease), only 27 percent developed progressive disease (eight with NLPHL and two with transformed disease), two developed secondary cancers, and none died. For patients who had treatment, 10 had disease transformation, 10 developed secondary cancers, and 7 died. It should be recognized that management was not randomly assigned and there may have been selection bias toward AS for patients who had a more favorable prognosis at the time of diagnosis.

In a multicenter study of 164 adults with NLPHL, long-term survival did not differ between patients on AS and those who received initial treatment [14]. With median follow-up of three years, 50 percent of patients with AS remained in complete remission (CR) without treatment. There was no difference with regard to 10-year OS (91 and 93 percent, respectively), but AS was associated with inferior 10-year PFS (41 versus 66 percent).

A study of 52 patients ≤21 years old with stage IA NLPHL reported 77 percent five-year event-free survival among children who had no residual disease after lymph node resection; no patient died during the observation period [12]. Other studies in children have reported similar outcomes with AS after surgical resection [9,11].

Surgical resection — Surgery has a role in management of NLPHL in selected settings.

Surgery alone is an acceptable option for younger patients with stage IA NLPHL whose disease was fully excised (ie, uninvolved margins) at the time of the diagnostic biopsy and for those who seek to avoid RT or other treatment. The choice of AS, RT, immunotherapy, or chemoimmunotherapy following complete resection of stage IA NLPHL must be individualized and should reflect concerns and wishes of the patient and/or family. Outcomes with AS following complete surgical resection are described above. (See 'Active surveillance' above.)

We generally suggest not performing additional surgery with the goal of achieving uninvolved margins in other settings (eg, incomplete resection, stage other than IA).

Radiation therapy — RT alone is effective for early stage disease and for relief of symptoms in patients with advanced stage NLPHL. (See 'Treatment stratification' above.)

We suggest involved-site RT (ISRT) or involved-node RT with doses of 30 to 36 Gy, in order to limit toxicity of larger fields or higher doses [6,15]. Larger RT fields provide no advantage but are associated with a greater risk of short-term and/or long-term toxicity [16-18]. Computed tomography (CT)-based simulation is used to determine target volumes and organs-at-risk. The clinical target volume definition should be generous, with inclusion of any sites that are suspicious of harboring microscopic disease. Intensity-modulated RT should be considered if target metrics of surrounding organs-at-risk cannot be met with 3-D conformal therapy. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

Outcomes with RT alone for early stage (I/II) NLPHL are excellent, with >95 percent OS at five or more years. Short-term toxicity varies with RT site(s), volume, and dose, but may include mucositis, nausea/vomiting, radiation dermatitis, and cytopenias. Long-term effects may include organ fibrosis and second malignancies, but there is little concern about cardiac toxicity of RT with NLPHL because mediastinal involvement is uncommon. It is expected that the smaller radiation fields and lower doses of RT used with contemporary techniques will result in fewer second malignancies than in most published studies.

A retrospective study of 257 patients treated with RT alone (30.6 to 36 Gy using involved site-, involved field-, or extended field-RT) for early-stage NLPHL reported 91 percent five-year progression-free PFS and >70 percent 10-year PFS; late toxicity included hypothyroidism in 3 percent, while <1 percent developed either xerostomia or heart disease (after mediastinal RT) [19]. Other, smaller studies using various doses and target volumes have reported similar outcomes and toxicity [18,20-23].

Retrospective studies that compared outcomes with RT alone versus either chemoimmunotherapy or CMT are described below. (See 'Combined modality therapy' below.)

Patients should undergo repeat positron emission tomography (PET) within three months of completing RT. Other aspects of monitoring are described below. (See 'Monitoring' below.)

Chemoimmunotherapy — There is no consensus regarding a preferred chemotherapy regimen for NLPHL, but we generally include rituximab because NLPHL cells consistently express CD20.

We favor treatment with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) based on the balance of efficacy and toxicity. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Chemoimmunotherapy'.)

Other acceptable options include:

R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), especially for patients with cardiac risk factors that may be exacerbated by an anthracycline.

Bendamustine plus rituximab (BR), based on activity with non-Hodgkin lymphoma. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Bendamustine plus rituximab'.)

ABVD (rituximab, doxorubicin, bleomycin, vinblastine, dacarbazine), but this regimen is associated with more neuropathy and pulmonary toxicity than R-CHOP. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'ABVD chemotherapy'.)

A retrospective review of cooperative group trials that preceded the routine use of rituximab reported that alkylator-containing chemotherapy was associated with fewer relapses than ABVD, but it is unclear if this observation is relevant when rituximab is included in the treatment regimen (eg, CHOP, CVP, BR) [24]. There is no evidence to support treatment of NLPHL with more aggressive regimens (eg, BEACOPP) that are used in classic Hodgkin lymphoma.

Restaging PET/CT should be performed after completion of planned chemoimmunotherapy, with subsequent follow-up as described below. (See 'Monitoring' below.)

All of the suggested regimens achieve high rates of CR and long-term OS, but no randomized studies have directly compared regimens or demonstrated the benefit of adding rituximab to chemotherapy. As examples:

R-CHOP was associated with 100 percent ORR (overall response rate; including 89 percent CR) in 27 patients with NLPHL; with median follow-up of 6.7 years, the estimated five-year and 10-year PFS rates were 89 and 60 percent, respectively [25].

CVP was associated with 100 percent ORR and 75 percent freedom from treatment failure (FFTF) at 40 months and 80 percent CR in 45 adult patients [26].

Treatment of 42 patients with stage IIB, III, or IV NLPHL, 27 of whom received ABVD, achieved 84 percent 10-year OS and 75 percent 10-year FFTF [27]. A case series of seven children with stage I/II NLPHL treated with six cycles of ABVD alone reported 100 percent CR, but with median follow-up of four years, 43 percent relapsed [28].

Combined modality therapy — CMT for NLPHL refers to treatment with both chemoimmunotherapy plus RT.

Instead of CMT, we generally prefer to treat NLPHL with either chemoimmunotherapy alone or ISRT alone, because of the late toxicity and mortality of CMT in patients with NLPHL. Compared with chemoimmunotherapy alone or ISRT alone, CMT achieves superior disease control, but provides no survival advantage and is associated with higher rates of short-term and long-term complications, including second malignancies and cardiac disease. It is difficult to predict long-term complications using contemporary approaches (in light of the larger target volumes and higher doses that were used in many of the published trials), but death as a result of a second malignancy (6 percent) or cardiac disease (4 percent) were as common as death from Hodgkin lymphoma (6 percent) or other causes (6 percent) [17,29-34].

No randomized trials have directly compared CMT with chemoimmunotherapy alone or ISRT alone. Retrospective studies have generally included limited numbers of patients, variable prognostic categories, different chemotherapy regimens and RT dosing, and diverse endpoints. A retrospective cooperative group study of early stage NLPHL compared outcomes in 257 patients treated with RT alone and 184 treated with CMT [19]. Both modalities achieved 91 percent five-year PFS, 99 percent OS, and comparable long-term toxicities, but RT alone was associated with more hypothyroidism (3 versus 0 percent) and more second cancers (6 versus 3 percent, but <1 percent of patients in both groups developed second cancers within the RT treatment volume). Another cooperative group study reported comparable eight-year PFS for stage IA NLPHL treated with IFRT (108 patients) or CMT (72 patients), but CMT was more toxic and appeared to be associated with more second malignancies (11 versus 4 percent) [20]. Another cooperative group study and various single institution studies also did not identify advantages for CMT [21,35,36].

Patients should undergo repeat PET within three months of completing chemoimmunotherapy. Other aspects of monitoring are described below. Long-term follow-up of patients treated with CMT is critical to monitor for disease recurrence, screen for second malignancies, and reduce other risk factors for the development of cardiovascular disease. (See 'Monitoring' below.)

Rituximab — Rituximab is a monoclonal antibody directed against CD20, an antigen that is uniformly expressed by NLPHL cells. We usually reserve the use of single-agent rituximab for patients who are not candidates for cytotoxic chemotherapy, selected patients with advanced disease, and for those with low volume recurrent disease. (See 'Advanced NLPHL' above and 'Relapsed NLPHL' below.)

Rituximab is generally given at 375 mg/m2 weekly for four doses. Toxicity of rituximab includes infusion reactions (ie, fevers, rigors, and hypotension) and infections related to immunosuppression. Rare cases of progressive multifocal leukoencephalopathy have been reported. Rituximab imposes a risk of hepatitis B reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Rituximab therapy is associated with high rates of response and OS, but a continued risk of relapse. Single-agent rituximab has achieved CR in more than two-thirds of patients, overall response (OR) in nearly all, and it is effective for both untreated and previously treated patients with NLPHL [37-40]. Rituximab is well tolerated with occasional infusion reactions. There are reports that rituximab maintenance therapy (eg, 375 mg/m2 every six months for two years) may be associated with transformation to aggressive B cell lymphoma, especially in patients with intra-abdominal disease.

Informative studies include:

Rituximab followed by rituximab maintenance therapy for 39 patients with NLPHL used maintenance therapy once every six months for two years [40]. OR was 100 percent (67 percent CR, 33 percent partial remission) with rituximab alone and estimated five-year PFS was 39 percent and 59 percent, respectively, for patients treated with rituximab alone versus rituximab plus maintenance. Corresponding five-year OS rates were 96 and 86 percent. There was a pattern of continued relapse and an unexplained high incidence of transformation to a more aggressive lymphoma subtype (23 percent) with a median time to transformation of 4.7 years.

A GHSG phase II trial of single-agent rituximab in 29 adults with stage IA NLPHL reported an OR of 100 percent (86 percent CR) [38]. At a median follow-up of 43 months, PFS at 36 months was 81 percent. Patients who relapsed were able to achieve a CR with radiation and/or chemotherapy.

Patients should undergo repeat PET/CT within three months of completing immunotherapy; other aspects of monitoring are described below. (See 'Monitoring' below.)

MONITORING — The follow-up schedule for NLPHL should be individualized based on the stage of disease, initial treatment modality, age, and comorbid illnesses. There are no guidelines or agreed-upon protocols for follow-up.

For all patients, we suggest follow-up visits:

Every 3 to 6 months for the first 2 years

Every 6 to 12 months until year 3

Annually for at least 5 years

Clinical evaluation at each visit should include interim history and physical examination, complete blood count (CBC), and chemistry profile as clinically indicated.

We suggest re-staging with positron emission tomography (PET) within three months of completing therapy:

For patients whose PET is negative, there is no consensus regarding a role for further imaging. Clinician and patient should weigh the reassurance provided by imaging against the risks of radiation exposures.

For patients with evidence of persistent disease, we suggest re-biopsy to determine if there is evidence of transformation to an aggressive lymphoma. Asymptomatic patients with a negative biopsy can be observed, while those with a positive biopsy should be managed as for relapsed or refractory disease. (See 'Relapsed/refractory disease' below.)

Some experts do not repeat a PET after completion of therapy, and there are no studies that have compared monitoring approaches. For patients undergoing active surveillance, there is no need for routine imaging.

We suggest follow-up with an experienced hematologist/oncologist for the first five years after treatment to detect recurrence. Subsequently, patients can be followed annually for late complications, including secondary cancers and cardiovascular disease. Surveillance for second malignancies and other treatment-related toxicities is described separately. (See "Approach to the adult survivor of classic Hodgkin lymphoma".)

RELAPSED/REFRACTORY DISEASE

Patterns of relapse — Although the prognosis for patients with NLPHL is generally excellent, a minority of patients may have a recurrence of the original disease or a histologic transformation to diffuse large B cell lymphoma (DLBCL). In general, relapses tend to occur late and may be distant from the initial site of presentation. The cause of death is often non-Hodgkin lymphoma (NHL), other cancers, or complications of treatment, rather than death from Hodgkin lymphoma [41-43].

Patients tend to develop late recurrences at sites distant from the original regions of presentation and can relapse repeatedly [14,17,44]. Retrospective studies show that the rates of freedom from treatment failure decline from 5 years (range 67 to 100 percent) to 10 years (45 to 88 percent) and to 15 years (71 to 82 percent) after treatment [7,16,17,22,29-31,45-48].

A review of 710 patients with NLPHL treated on 12 prospective German trials reported primary refractory disease in 1 percent and relapse in 15 percent with a median time to recurrence of 3.7 years [23].

Transformation — The cause of death of patients with NLPHL is often a transformed, aggressive NHL [13,41-43,49,50].

Transformation to a large cell lymphoma is most common [14]. Most cases have a B cell immunophenotype, with monotypic immunoglobulin expression in approximately 30 to 50 percent. In some cases, a clonal relationship between the NLPHL and the large cell lymphoma has been shown by molecular analysis [51]. Patients with NLPHL have a higher risk of development of NHL than patients with other types of Hodgkin lymphoma [14,41-43,49,52-54].

Splenic involvement has been associated with the risk of transformation to aggressive B cell lymphoma [40]. In a study of 95 patients with a median follow-up of 6.5 years, transformation to aggressive lymphoma was seen in 14 percent of patients with median time to transformation of 8 years (range 0.4 to 20 years) [49]. The actuarial risk of transformation to aggressive lymphoma was 7 percent and 30 percent at 10 and 20 years, respectively.

Importance of re-biopsy — For patients who fail to respond to initial therapy or who develop recurrent disease after treatment or during active surveillance, we suggest repeat biopsy to confirm the diagnosis and determine if there is transformation to DLBCL. We also suggest repeat biopsy for the patient who has B symptoms, because this is rarely associated with NLPHL alone.

We strongly encourage an excisional lymph node biopsy, when possible. Distinguishing NLPHL from transformation to DLBCL and other conditions in the differential diagnosis relies on morphologic differences that may be difficult to appreciate in core biopsies and fine needle aspiration (FNA).

Patients with a negative biopsy can be monitored, as described above. (See 'Monitoring' above.)

Patients with biopsy-proven NLPHL or transformed lymphoma should be restaged and treated according to histologic appearance and prior treatment, as described below. (See 'Treatment of relapse' below.)

Treatment of relapse — Prior to treatment for relapsed disease, the patient should undergo a repeat biopsy. (See 'Importance of re-biopsy' above.)

Relapsed NLPHL — Treatment of relapsed or refractory NLPHL is guided by the biopsy findings, burden of disease, medical comorbidities, and prior therapy.

We generally include induction treatment with rituximab (375 mg/m2 weekly for four treatments) for all patients with relapsed NLPHL. Some experts suggest adding maintenance rituximab (eg, 375 mg/m2 every six months for two years), but there is concern that maintenance therapy may be associated with disease transformation, especially in patients with splenic involvement. (See 'Transformation' above.)

Our approach follows:

Localized disease – For a localized disease recurrence, involved-site radiation therapy (ISRT) to a dose of 30 to 36 Gy is associated with excellent disease control and is suggested for patients who did not previously receive radiation therapy (RT) at that site. For recurrence at a site of previous radiation, we suggest systemic therapy, as described for extensive disease.

Extensive disease – Patients who are chemotherapy-naïve should be treated with rituximab with chemotherapy, but some may be treated with rituximab alone, based on the pace and burden of disease and symptoms. ISRT may be added for symptomatic sites.

Patients who were treated initially with RT may be treated with R-CHOP or other conventional chemotherapy. We generally use noncross-resistant chemotherapy for salvage, so that a patient who initially was treated with R-CHOP might receive R-CVP or BR. (See 'Chemoimmunotherapy' above.)

Subsequent relapses of NLPHL can be treated as described below, and patients are usually candidates for high-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT). (See 'Transformed lymphoma' below.)

A retrospective study of 91 patients treated for relapsed NLPHL with a variety of approaches reported five-year PFS and OS 76 and 90 percent, respectively [23]. Other informative studies include:

Single-agent anti-CD20 antibody treatment achieves a response in nearly all patients with relapsed/refractory NLPHL and, for some, the response is sustained. In a study of 39 patients with relapsed NLPHL, rituximab induction achieved complete response (CR) in 67 percent and overall response (OR) in 100 percent [40]. Maintenance rituximab may sustain remissions, but it appears to be associated with an increased risk for transformation to DLBCL. In a study of 21 patients with relapsed NLPHL, compared to rituximab induction alone, maintenance rituximab achieved superior PFS (59 versus 39 percent), but similar overall survival (OS; 86 and 96 percent) [37].

Five-year PFS and OS were 74 and 97 percent, respectively, with single-agent rituximab or RT alone; 68 and 78 percent, respectively, for chemoimmunotherapy; and 85 and 90 percent for HCT. Another report of autologous HCT for relapsed NLPHL in 60 patients reported that 62 percent of patients achieved CR and 38 percent partial remission, and five-year PFS and OS were 66 and 87 percent; CR at the time of transplant was the only predictor of outcome [55].

Children with relapsed NLPHL also respond well to RT or chemotherapy [56].

Transformed lymphoma — There is no consensus regarding the optimal management of transformed DLBCL that arises from NLPHL.

Patients with transformed lymphoma who had already received chemotherapy as part of their NLPHL treatment usually are candidates for high dose chemotherapy followed by autologous HCT. Treatment may include salvage regimens, such as R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) or R-DHAP (rituximab, dexamethasone, high dose cytarabine, cisplatin), as used in DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Most NLPHL patients with histological transformation at disease recurrence respond successfully to salvage treatment. In one series, 26 patients with relapsed lymphoma (18 with NLPHL, 8 with DLBCL) underwent high dose chemotherapy with autologous HCT and five-year PFS and OS rates were 61 and 73 percent in NLPHL and 73 and 87 percent in patients with transformed disease [57]. Analysis of 17 patients with transformed NLPHL reported five-year OS rate of 76 percent [54]. According to another report of 13 patients with histological transformation into aggressive B cell NHL, the 10-year PFS and OS rates were 52 and 62, percent, respectively [49].

Several small retrospective studies have evaluated the prognosis of patients with DLBCL arising in the context of transformed NLPHL. In one study, patients with transformed NLPHL who were treated aggressively with curative chemotherapy appeared to have similar survival outcomes as those who were diagnosed with de novo DLBCL [50]. The prognosis was better in a second, larger retrospective study, which reported that the survival rates for patients with transformed NLPHL were similar to those of non-transformed NLPHL (median survival approximately 19 years in both groups) [54]. The superior outcomes in the latter may reflect differences in patient population and treatment. As an example, the use of rituximab was much more common in the latter study (82 versus 46 percent).

PROGNOSIS — NLPHL generally has a good prognosis and is associated with better outcomes than classic Hodgkin lymphomas (cHL). This is due, in part, to the biologic characteristics of NLPHL, but also to the distribution of prognostic factors, since patients with NLPHL are less likely to present with advanced stage disease, B symptoms, or bulky disease.

Outcomes are more favorable for early stage disease than for advanced NLPHL. In a retrospective analysis of 394 patients with NLPHL, complete remission (CR) was achieved in 92 percent with favorable early stage disease, 86 percent with unfavorable early stage, and 77 percent with advanced stage disease [8]. Overall survival (OS) at four years was 96 percent; 31 deaths occurred among the NLPHL patients including 8 due to HL and 10 from secondary malignancies, including leukemia/myelodysplastic syndromes, non-Hodgkin lymphoma, and solid tumors. In another study, freedom from treatment failure (FFTF) was superior for early stage favorable disease (93 percent) compared with early stage unfavorable (87 percent) and advanced stage disease (77 percent) [45]. Patients with stages I to III disease have relapse rates that range from 15 to 38 percent, but OS rates are in the range of 94 to 99 percent, since relapses are almost always responsive to further treatment. The European Task Force on Lymphoma also reported more favorable outcomes for early stage disease compared with advanced stage [7]. Advanced stage at presentation, age ≥45 years, low hemoglobin, and presence of B symptoms were associated with worse OS [8,44]. Relapses with NLPHL are generally later than for cHL [27]. Histologic variants of NLPHL (eg, presence of lymphocyte predominate [LP] cells outside the B cell nodules and/or reduced numbers of non-neoplastic B cells in the nodules) are associated with inferior outcomes, in part, because these patients tend to present with more advanced disease and other adverse prognostic features [58].

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".)

SUMMARY AND RECOMMENDATIONS

Description – Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon and generally indolent subtype of Hodgkin lymphoma (HL), which has pathologic features, natural history, and management that are distinct from those of classic HL (cHL).

Evaluation – Staging is according to Lugano criteria (table 1). (See 'Staging and pretreatment evaluation' above.)

Management – Stratified by disease stage and prognostic factors (see 'Overview of treatment' above):

Non-bulky early stage NLPHL – Non-bulky (ie, <10 cm) stage IA disease or non-bulky, contiguous stage IIA disease without significant disease-related symptoms and no mass lesions that threaten organ compromise (eg, compression of airway or ureters).

Bulky or non-contiguous early stage NLPHL – Other stage I or stage II NLPHL, such as ≥10 cm mass, non-contiguous disease, disease-related symptoms, or organ-threatening mass.

Advanced NLPHL – Stage III or stage IV disease

Non-bulky early stage NLPHL – We suggest involved-site radiation therapy (ISRT) or active surveillance (AS), rather than chemoimmunotherapy or combined modality therapy (CMT; ie, chemoimmunotherapy plus radiation therapy) (Grade 2C). (See 'Non-bulky early stage NLPHL' above.)

Bulky or non-contiguous early stage NLPHL – We suggest chemoimmunotherapy or ISRT, rather than CMT (Grade 2C). (See 'Bulky or non-contiguous early stage NLPHL' above.)

We generally treat with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), but R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), R-B (bendamustine plus rituximab), or ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) are acceptable. Single-agent rituximab or AS is acceptable for patients with modest or no symptoms, those who cannot tolerate more aggressive treatments, or patients who value avoidance of toxicity more than the burden of symptoms.

Advanced NLPHL – Guided by severity of symptoms (see 'Advanced NLPHL' above):

Symptomatic – We suggest chemoimmunotherapy rather than ISRT or CMT (Grade 2C).

For symptomatic patients who do not want or cannot tolerate more aggressive treatments, either single-agent rituximab or rituximab plus ISRT to locally symptomatic disease is acceptable.

Asymptomatic or minimally symptomatic – We consider chemoimmunotherapy, single-agent rituximab, or AS acceptable, with selection individualized to reflect patient preferences. Some experts avoid treatment with rituximab alone for patients with splenic involvement because of a possible association with transformation to more aggressive histology.

Treatments

Surgery – (See 'Surgical resection' above.)

Radiation therapy (RT) – (See 'Radiation therapy' above.)

Chemoimmunotherapy – (See 'Chemoimmunotherapy' above.)

Combined modality therapy (chemoimmunotherapy plus RT) – (See 'Combined modality therapy' above.)

Rituximab – (See 'Rituximab' above.)

Monitoring – We repeat positron emission tomography (PET) after completing therapy. Other aspects of monitoring are described above. (See 'Monitoring' above.)

Relapse

Diagnosis – Repeat biopsy to exclude transformation to a more aggressive histology (eg, diffuse large B cell lymphoma). (See 'Importance of re-biopsy' above.)

Management - Informed by biopsy findings, extent of disease, symptom burden, pace of progression, prior therapy, and comorbid illnesses. (See 'Treatment of relapse' above.)

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

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References

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