Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B cell-derived malignancy accounting for ∼5% of all Hodgkin lymphoma (HL) cases. Pathological and clinical characteristics of NLPHL differ from classical HL (cHL) .
The malignant cells in NLPHL are termed lymphocyte predominant (LP) cells. They stain consistently positive for CD20 but lack CD30 (Table 1). Six different histopathological growth patterns have been described in NLPHL . Patients with a typical histopathological growth pattern (pattern A and B according to Fan et al.) are distinguished from individuals with a variant histology (pattern C, D, E and F according to Fan et al.). The diagnosis of NLPHL with a variant histology can be difficult since especially growth pattern E closely resembles T-cell and histiocyte-rich large B-cell lymphoma. Additional differential diagnoses of NLPHL include benign conditions such as the progressive transformation of germinal centers and other lymphomas such as lymphocyte-rich cHL. The clinical course of NLPHL is usually rather indolent. However, there is a tendency toward late and multiple relapses. In addition, histological transformation into aggressive B-cell non-Hodgkin lymphoma (B-NHL) occurs in a significant minority of patients . In comparison with cHL, NLPHL is diagnosed at a higher median age (43 years according to an analysis using the SEER database) and patients are more often male (∼75% of cases) . At initial diagnosis, patients mostly present with early-stage disease .
Table 1 -
Pathological markers in nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma
||cHL (H-RS cells)
||NLPHL (LP cells)
NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma
This review aims at summarizing and discussing the most recent publications addressing the management of NLPHL.
FIRST-LINE TREATMENT OF NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA
Patients with newly diagnosed NLPHL are treated with stage-adapted approaches. Treatment differs from cHL in some situations (Table 2).
Table 2 -
Treatment of newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma
||Treatment of choice
|Stage IA without risk factors
||Limited-field RT alone
||2 × (R)-ABVD + RT
||4 × (R)-ABVD + RT
||Interim PET-guided escalated BEACOPPa 6 × R-CHOPb
aIn younger patients if disease control represents the major goal.
bIn older patients and in patients ineligible for or refusing escalated BEACOPP.
Treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma without risk factors
Stage IA NLPHL without risk factors is usually treated with limited-field radiotherapy (RT) alone. Several analyses have indicated that the addition of chemotherapy does not improve the outcome of this patient group. The largest analysis was performed by the German Hodgkin Study Group (GHSG). 49 patients treated with extended-field RT, 108 patients who had involved-field RT and 72 patients who had combined-modality treatment were included. At 8 years, progression-free survival (PFS) was roughly 90% and overall survival (OS) was close to 100%. There were no differences between the treatment groups . A recent retrospective analysis comprising 36 patients evaluated the possibility of a further reduction of the RT field. Patients had extended-field RT (n = 9), involved-field RT (n = 13) or involved-site RT (n = 14). The 5-year PFS estimates were similar for all three groups . However, since the median observation time for patients receiving IS-RT was only 2.6 years, additional analyses with a longer follow-up are required to answer the question of whether IS-RT alone is sufficient for stage IA NLPHL without risk factors.
Different prospective studies including patients with stage IA NLPHL without risk factors aimed at decreasing treatment toxicity without compromising efficacy. A phase II study from the GHSG investigated single-agent anti-CD20 antibody treatment with rituximab in 28 patients. All patients responded to 4 weekly standard doses (375 mg/m2) . However, long-term disease control was worse than with RT alone. At 10 years, the PFS was only 51.1%. The 10-year OS was 91.0% and thus not impaired since relapses were salvaged successfully . A resection only approach was evaluated in a study including children and adolescents. A total of 52 patients with NLPHL affecting a single lymph node who had a complete remission (CR) after surgical resection as confirmed by computed tomography (CT) and positron emission tomography (PET) were followed after surgery and did not receive consolidation RT or chemotherapy. The 5-year event-free survival was 77.1%. The 5-year OS was 100% .
Overall, limited-field RT alone represents the current standard approach for stage IA NLPHL without risk factors at many institutions [11,12]. Resection alone can be discussed on a case-by-case basis in patients with a CR after surgical resection of the affected lymph node.
Treatment of nodular lymphocyte-predominant Hodgkin lymphoma in early stages other than stage IA without risk factors and intermediate stages
In NLPHL patients diagnosed in early stages other than stage IA without risk factors and intermediate stages, combined-modality treatment consisting of a brief chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or ABVD-like protocols followed by consolidation RT appears to result in a better disease control than RT alone [13,14]. Thus, two cycles of ABVD for early stages other than stage IA without risk factors and four cycles of ABVD for intermediate stages each followed by limited-field RT are often given. Outcomes are excellent. A long-term analysis including 251 NLPHL patients treated within the randomized GHSG HD7, HD10, and HD13 studies for early-stage HL indicated 10-year PFS and OS rates of 79.7% and 93.3%, respectively. The 10-year PFS and OS rates for 76 patients with intermediate-stage NLPHL treated within the randomized GHSG HD8, HD11 and HD14 studies were 72.1% and 96.2%, respectively [15▪▪]. A report from the International Lymphoma Radiation Oncology Group investigating the outcome of patients with stage I/II NLPHL revealed a 5-year PFS of 90.5% and a 5-year OS of 99.4% after combined-modality treatment [16▪]. The question of whether the addition of an anti-CD20 antibody to standard chemotherapy results in improved outcomes of patients with NLPHL in early stages other than stage IA without risk factors and intermediate stages is unanswered since larger analyses addressing this issue are pending.
Treatment of nodular lymphocyte-predominant Hodgkin lymphoma in advanced stages
Patients with advanced-stage disease account for ∼25% of NLPHL cases. The optimal management strategy for these patients is subject to ongoing discussions . Both, HL and B-NHL-directed protocols are given depending on the institution's preference.
A retrospective analysis from Canada included 42 patients with advanced NLPHL who had been treated with ABVD or ABVD-like protocols. The 10-year lymphoma recurrence rate with either NLPHL histology or histological transformation into aggressive B-NHL was ∼40%. The 10-year OS was 83.5%. . Disease control with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) variants seems to be better. An analysis comprising 144 patients with advanced NLPHL who had been included in the randomized GHSG HD7, HD10, and HD13 studies revealed 10-year PFS and OS rates of 69.8% and 87.4%, respectively. Only 1.4% of patients developed histological transformation into aggressive B-NHL [15▪▪]. Promising results were also obtained with interim PET-guided escalated BEACOPP. According to an analysis comprising 84 patients treated within the randomized GHSG HD18 study, the 5-year PFS and OS rates with this approach were 82.4% and 92.4%, respectively. The majority of patients had a negative interim PET after 2 cycles of chemotherapy. For these patients, treatment reduction to a total of only 4 cycles of escalated BEACOPP did not result in a loss of disease control so that the current GHSG standard approach for patients with advanced cHL consisting of 4 (in case of a negative PET after 2 cycles of chemotherapy) or 6 (in case of a positive PET after 2 cycles of chemotherapy) cycles of escalated BEACOPP also represents a valid option for individuals with NLPHL [18,19▪]. Given the consistent expression of CD20 on the malignant LP cells, some institutions prefer the use of B-NHL-directed regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and BR (bendamustine, rituximab) in advanced NLPHL. However, only limited data are available for these approaches. A retrospective analysis from a single institution in the US included 14 patients with stage III/IV NLPHL who had received R-CHOP. The 5-year PFS was 85.7%. The 5-year OS exceeded 90% . A case series from Finland reported the outcomes of 8 patients with stage III/IV NLPHL who had been treated with BR. All patients had responded to treatment and no relapse had occurred after a median observation time of 34 months .
Taken together, the largest body of evidence regarding the first-line treatment of advanced NLPHL is available for escalated BEACOPP. This intensive protocol should be considered in younger patients when disease control and potential cure represent the major goal of therapy. Treatment with R-CHOP or BR can be discussed in older patients and those who are not eligible for or refuse escalated BEACOPP.
TREATMENT OF RELAPSED NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA
NLPHL recurrence mostly occurs several years after the initial treatment [22–24]. Single-agent anti-CD20 antibody treatment, RT alone, or conventional chemotherapy optionally combined with an anti-CD20 antibody and/or RT represent sufficient salvage approaches in the majority of patients with relapsed NLPHL [23,24]. The use of high-dose chemotherapy and autologous stem cell transplantation (ASCT) is restricted to high-risk patients presenting with adverse factors. Those include a time interval of less than 2 years between first-line treatment and disease recurrence, liver and/or bone marrow involvement as well as signs of histological transformation into aggressive B-NHL [15▪▪].
Anti-CD20 antibodies given as single agent have been evaluated in different phase II studies. A study from the GHSG included 15 patients with NLPHL recurrence. Patients had 4 weekly standard doses of rituximab. The overall response rate (ORR) was 94%. After a median follow-up of 63 months, the median time to progression was 33 months . Similar results were obtained from another prospective study investigating rituximab in both, patients with newly diagnosed and relapsed NLPHL . A study evaluating the second-generation anti-CD20 antibody ofatumumab in 28 patients with NLPHL recurrence revealed an ORR of 96% after 8 weekly doses. The 2-year PFS and OS estimates were 80% and 100%, respectively . Several retrospective analyses have consistently demonstrated that RT alone and conventional chemotherapy induce long-term disease control in a relevant proportion of patients with relapsed NLPHL [23,24]. These approaches can therefore also be considered in the case of NLPHL recurrence. The use of high-dose chemotherapy and ASCT is restricted to poor-risk patients. The largest analysis retrospectively evaluating this modality came from the European Society for Blood and Marrow Transplantation. A total of 60 patients were included. After a median observation time of 56 months, the 5-year PFS and OS rates were 66% and 87%, respectively . Additional analyses also addressing high-dose chemotherapy and ASCT in relapsed NLPHL had similar results [29,30]. Other approaches that may be discussed in individual patients with relapsed NLPHL have been reported in smaller case series. For instance, long-term remission has been achieved with CD20-directed radioimmunotherapy .
In summary, there is no standard approach for the treatment of relapsed NLPHL (Fig. 1). Different factors should be taken into consideration when treatment is chosen for the individual patient. Those include time to relapse, previous treatment as well as disease localization and clinical presentation at relapse. The prognosis after NLPHL recurrence is still very good. Two large retrospective analyses including 99 and 69 patients reported 5-year PFS rates of 75.6% and 68% and 5-year OS rates of 89.5% and 94%, respectively [23,24].
Generally, NLPHL is associated with an excellent prognosis. The vast majority of patients are alive at 10 years. However, the optimal management strategy is undefined for some situations. Treatment of NLPHL can possibly be optimized by the implementation of anti-CD20 antibodies. In addition, a better risk group allocation that may differ from cHL could result in a reduction of treatment intensity in a relevant proportion of patients. Risk scores for individuals with NLPHL could include parameters such as the histopathological growth pattern that was shown to have significant prognostic impact .
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Conflicts of interest
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REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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