Abstract

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon entity that, in contrast to classical Hodgkin lymphoma (cHL), universally expresses CD20, a hallmark of the disease. The majority of the patients present with early-stage disease, and treatment with local radiation provides excellent disease control and overall survival (OS). For locally extensive or advanced stages, paradigms used for cHL have been employed, with similar outcomes. Unlike cHL, late relapses may occur, as well as a propensity to transform to an aggressive B-cell non-Hodgkin lymphoma that underscores the importance of long-term follow-up and rebiopsy at the time of relapse. Deaths caused by NLPHL are uncommon, and in older series, secondary malignancies and other treatment-related toxicities contributed appreciably to overall mortality. Expression of CD20 in NLPHL has led to the evaluation of rituximab as a therapeutic option. Although results with single-agent rituximab in the front-line setting are inferior to conventional therapy, rituximab is a reasonable choice for relapsed disease because of the high overall response rate and excellent tolerability. Most patients have a long OS; therefore, overall goals of therapy should be to minimize the risk for relapse and long-term toxicity.

Introduction

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a unique entity representing ∼5% of Hodgkin lymphoma (HL). The largest review defining characteristics was reported by the European Task Force on Lymphoma Project on lymphocyte predominant HL (LPHL) and included data from 426 patients initially diagnosed with LPHL from 17 European and US centers.1  After expert pathology revision and the availability of immunohistochemistry (IHC), only 219 cases (51%) were confirmed to be LPHL. Therefore, extrapolation of results of earlier studies, performed in an era when stringent IHC criteria were not used, to current management strategies is of limited value.

Pathobiology

An excisional biopsy is essential, along with evaluation by an expert hematopathologist. NLPHL is notable for a distinct malignant cell originally termed lymphocytic and histiocytic and reclassified in the World Health Organization 2008 classification as LP (lymphocyte predominant) cells.2  Because of their microscopic appearance and increased number of nucleoli, a more descriptive term, “popcorn cells,” has been used. At least 1 nodule containing a mixture of LP cells and small B cells is required for a diagnosis of NLPHL. LP cells are seen in a background of B-cell-rich lymphoid follicles associated with follicular dendritic cell meshworks.3,4  Some reports propose the recognition of intrafollicular neoplasia/in situ NLPHL, associated with early-stage disease and favorable outcome.5  Single-cell polymerase chain reaction assays demonstrate clonally rearranged immunoglobulin genes that variably express immunoglobulin mRNA.6-9  Different chromosomal abnormalities have been described in two-thirds of cases. Although some genetic lesions have been identified, little is known about the pathogenesis of LP cells. Constitutive activity of nuclear factor κB, Janus kinase/signal transducer and activator of transcription pathway, and BCL-6 transcription factors appear to be involved; however, mutations in the genes coding for nuclear factor κB regulating factors inhibitory nuclear factor κB α and A20 are uncommon.10  Recently, a germ-line candidate mutation in the nuclear protein ataxia telangiectasia gene locus has been identified in familial NLPHL.11 

Immunophenotyping is critical for establishing a diagnosis.12  Unlike malignant Reed-Sternberg cells in classical HL (cHL), LP cells lack expression of CD15, CD30, and Epstein-Barr virus.3  A typical B-cell phenotype is seen, and cells express CD20, CD45, CD75, and often, J-chain.3  Epithelial membrane antigen is present in ∼50% of cases.13  Recently, some cases expressing CD15 have been reported and associated with a more aggressive clinical course.14  B-cell transcription factors, such as Oct 2a, are overexpressed and are therefore very important diagnostic markers in the search for LP cells in biopsies.13  A diffuse growth pattern with prominent histiocytes and T cells is seen during the evolution of NLPHL and is often difficult to distinguish from T-cell-rich B-cell lymphoma (TCRBCL).3  Unlike TCRBCL, the meshwork of follicular dendritic cells and B cells is retained with CD4+, CD57+, and PD1+ rosette-forming T cells.3  Immunophenotypical and molecular studies demonstrate a LP-cell immunophenotype and a clonal relationship between LP cells and cells of concurrent or subsequent diffuse large B-cell lymphoma (DLBCL), suggesting a common cell of origin.15,16  Progressive transformation of germinal centers (PTGCs) can be mistaken for NLPHL. However, its distinction from NLPHL is reliably possible by immunophenotyping, as the transformed germinal centers do not harbor cells expressing the typical immunophenotype of LP cells, and occasionally, PTGC and NLPHL may exist in the same lymph node.17 

Clinical features

The estimated incidence of NLPHL is ∼1.5 per 1 000 000 people per year.1  In a Finnish registry, the standardized incidence ratio for NLPHL was 19 (95% confidence interval, 8.8-36) in first-degree relatives compared with 5.3 (95% confidence interval, 3-1.8) for cHL, warranting further evaluation of potential genetic and environmental factors.18  Asymptomatic adenopathy can precede diagnosis by months to years. The largest series is a retrospective analysis by the German Hodgkin Study Group (GHSG) in which 394 patients with NLPHL were compared with 7904 patients with cHL. The median age was 37 years, and 75% of the patients were male.19  The majority (63%) had early-stage favorable, 16% early-stage unfavorable, and 21% advanced-stage disease. In contrast, more patients with cHL had early unfavorable (39%) or advanced (39%) disease.

In the European Task Force on Lymphoma Project on LPHL, peripheral lymph node sites were most often affected, and in contrast to cHL, significantly fewer patients had B symptoms or extranodal sites of disease. Mediastinal disease was extremely rare, seen only in ∼7% of patients.1  Splenic involvement can be seen and may be associated with occult transformation to an aggressive, large-cell non-HL (NHL).20  NLPHL is fluorodeoxyglucose (FDG) avid, although the standardized uptake values are generally lower than those observed in cHL. FDG-positron emission tomography (PET) scanning is useful for staging and response assessment in NLPHL; however, the addition of PET imaging has led to alteration of therapy in only ∼10% of cases in comparison with use of computed tomography (CT) scanning alone.21,22 

Prognostic factors

Early-stage NLPHL has an excellent prognosis. Unfavorable risk factors have been reported as less common in NLPHL than in cHL: 3 nodal areas (28% vs 55%), elevated erythrocyte sedimentation rate (4% vs 45%), extranodal involvement (6% vs 14%), and elevated lactate dehydrogenase (16% vs 32%).19  A comparison of limited-stage cHL without mediastinal involvement and limited-stage NLPHL showed no overall survival (OS) differences.23  Similarly, no differences in OS were seen in the GHSG studies between early-stage favorable and unfavorable risk groups of LPHL and cHL.19  Freedom from treatment failure (FFTF) and OS were worse for patients with advanced-stage disease, hemoglobin levels lower than 10.5 g/dL, or lymphopenia (<8% of white cell count). Age 45 years or older was a negative prognostic factor only for OS.19  In another study of 88 patients with NLPHL, stage, low albumin, presence of B-symptoms, and poor initial response to treatment were factors associated with an inferior OS.24  A recent study reported that a peripheral blood absolute lymphocyte count/monocyte ratio of 2 or higher remained an independent prognostic factor for OS, progression-free survival (PFS), and time to progression after adjusting for International Prognostic Score. If validated, this blood test could potentially be used as a simple biomarker for risk stratification.25 

Transformation to aggressive NHL

Despite a favorable prognosis, it is recognized that NLPHL can transform into aggressive NHL as late as 2 decades after initial diagnosis. The subtype of DLBCL most frequently seen is TCRBCL.26,27  In a French registry-based analysis of pathological rereview of 164 patients diagnosed in 1973-2003, 19 of 66 patients with recurrence presented with histological transformation to an aggressive lymphoma at a median of 4.7 years after initial diagnosis. The OS was inferior compared with those with persistent NLPHL histology at the time of relapse.28  In a report from the British Columbia Cancer Agency (BCCA), 13 of 95 NLPHL cases experienced transformation into aggressive NHL at a median of 8.1 years.20  The actuarial risks for transformation were 7%, 15%, and 31% at 10, 15, and 20 years, respectively. Unfavorable risk factors for transformation included splenic involvement (P = .006) and advanced-stage disease (P = .057) at initial diagnosis. As in the previous report, prognosis was worse for patients with transformation than for those with relapsed NLPHL. After treatment with multiagent chemotherapy, followed in many cases by high-dose chemotherapy and autologous stem cell transplantation (ASCT), the 10-year estimates for PFS and OS were 52% and 62%, respectively.20  The Stanford group has reported abdominal involvement as a risk factor for transformation.29  In a study evaluating rituximab as a single agent, 6 patients with abdominal disease at study entry had evidence of transformation at recurrence. Collectively, these transformation rates underscore the importance of long-term follow-up of patients with NLPHL and rebiopsy at the time of relapse.

Therapy

Given the rarity of NLPHL, there are very few prospective studies to guide decision-making. In addition, many of the older series are of limited value, as the diagnosis of NLPHL was made in the pre-IHC era. Although a rationale for management of limited disease with local irradiation alone was proposed in the mid-1980s,30  in large clinical trials as recently as 2003, NLPHL was not treated differently than cHL.31  More recently, different treatment algorithms have been used for NLPHL, especially in limited-stage disease. Depending on stage, therapy has consisted of radiation therapy (RT), combined modality therapy (CMT), and chemotherapy alone. The expression of CD20 has added rituximab to the armamentarium of options. Management differs for early versus advanced stages and for front-line versus relapsed disease (Tables 1 and 2).

Table 1

Selected studies in stage I to II NLPHL

nMedian follow-up, yTreatmentOutcome (%)OS (%)Comments
Chen et al, 201034  113 11.3 RT 82% 10 y PFS Limited RT, 64 Limited RT, 100 Extent of RT did not affect PFS or OS. CMT did not affect PFS but was associated with worse OS 
CMT 12% Regional RT, 84 Regional RT, 95 
CHT 6% Extended RT, 81 Extended RT, 95 
CHT only, 14 CHT only, 83 
Nogova et al, 200532  131 3.6 RT 69% 2 y FFTF EFRT, 100 100 Included only stage IA without risk factors 
CMT 31% IFRT, 92 
CMT, 97 
Feugier et al, 200423  42 NA CMT 15 y FFP 80 86 Brief chemo and EFRT 
Wilder et al, 200244  48 9.3 RT 77% 10 y RFS RT, 77 90 Variable radiation field size 
CMT 23% CMT, 68 100 
Wirth et al, 200535  202 15 RT 15 y FFP 82 83 No effect of radiation field size 
Savage et al, 201145  51 5.7 CHT+/− RT 10 y PFS 93 93 Patients treated with CT only had negative interim PET scans 
35 18.6 RT only 77.5 85 
Shankar et al, 201246  55 3.3 CHT 3.3 y FFTF 75.4 100 All children, <18 y 
Mauz-Korholtz et al, 200742  58 3.6 Excision 4.2 y PFS 57 100 All children, <18 y 
nMedian follow-up, yTreatmentOutcome (%)OS (%)Comments
Chen et al, 201034  113 11.3 RT 82% 10 y PFS Limited RT, 64 Limited RT, 100 Extent of RT did not affect PFS or OS. CMT did not affect PFS but was associated with worse OS 
CMT 12% Regional RT, 84 Regional RT, 95 
CHT 6% Extended RT, 81 Extended RT, 95 
CHT only, 14 CHT only, 83 
Nogova et al, 200532  131 3.6 RT 69% 2 y FFTF EFRT, 100 100 Included only stage IA without risk factors 
CMT 31% IFRT, 92 
CMT, 97 
Feugier et al, 200423  42 NA CMT 15 y FFP 80 86 Brief chemo and EFRT 
Wilder et al, 200244  48 9.3 RT 77% 10 y RFS RT, 77 90 Variable radiation field size 
CMT 23% CMT, 68 100 
Wirth et al, 200535  202 15 RT 15 y FFP 82 83 No effect of radiation field size 
Savage et al, 201145  51 5.7 CHT+/− RT 10 y PFS 93 93 Patients treated with CT only had negative interim PET scans 
35 18.6 RT only 77.5 85 
Shankar et al, 201246  55 3.3 CHT 3.3 y FFTF 75.4 100 All children, <18 y 
Mauz-Korholtz et al, 200742  58 3.6 Excision 4.2 y PFS 57 100 All children, <18 y 

CHT, chemotherapy; NA, not reported/not available.

Table 2

Selected studies in stage III to IV NLPHL

nMedian follow-up, yTreatmentOutcome (%)OS (%)
Diehl et al, 19991  44 6.8 CHT or CMT* 8 y FFTP Stage III, 62 Stage III, 94 (DSS) 
Stage IV, 24 Stage IV, 41 (DSS) 
Nogova et al, 200819  83 4.2 CMT 4.2 y FFTF 77 96 
Canellos et al, 201050  37 NA 32%, ABVD or EVA  “Failure” 75 NA 
68%, MOPP+/ABVD “Failure” 32 NA 
Fanale et al, 201051  12 3.5 RCHOP +/IFRT 5 y PFS 95 95 
Xing et al, 201249  42 10 83%, ABVD 10 y FFTF 76 86 
nMedian follow-up, yTreatmentOutcome (%)OS (%)
Diehl et al, 19991  44 6.8 CHT or CMT* 8 y FFTP Stage III, 62 Stage III, 94 (DSS) 
Stage IV, 24 Stage IV, 41 (DSS) 
Nogova et al, 200819  83 4.2 CMT 4.2 y FFTF 77 96 
Canellos et al, 201050  37 NA 32%, ABVD or EVA  “Failure” 75 NA 
68%, MOPP+/ABVD “Failure” 32 NA 
Fanale et al, 201051  12 3.5 RCHOP +/IFRT 5 y PFS 95 95 
Xing et al, 201249  42 10 83%, ABVD 10 y FFTF 76 86 

ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone; COPP, cyclophosphamide, vincristine, procarbazine, and prednisone; DSS, disease-specific survival; EVA, etoposide, vinblastine, and adriamycin; IMEP, isophosphamide, methotrexate, etoposide, and prednisone; MOPP, mechlorethamine, vincristine, procarbazine, and prednisone; NA, not reported/not available; RCHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

*

CHT, chemotherapy; MOPP-, ABVD-, or MOPPABVD-like.

CMT; radiotherapy and COPP/ABV (doxorubicin, bleomycin, and vincristine)/IMEP, COPP/ABVD, or BEACOPP.

Treatment of early-stage disease

Radiation therapy

Historically, in the early 1960s, RT management of limited-stage NLPHL was not distinguished from that used for cHL. Treatment evolved from “involved-field” irradiation (IFRT) to “extended-field” (EFRT), “subtotal,” or “total lymphoid” irradiation as the more extensive radiation fields were associated with a superior outcome. However, as NLPHL was identified as a distinct entity, with characteristic presentation, response to therapy, and pattern of relapse, it was also appreciated that excellent outcomes were often achieved with limited RT.

In a retrospective review by the GHSG on the Hodgkin disease (HD)-4 and HD-7 trials, the 2-year FFTF/OS for IFRT versus EFRT was 92%/100% and 100%/94%, respectively.32  This was an important observation, as more-aggressive initial therapy was associated with greater toxicity and fatality. In fact, in a large European-American retrospective study in which the median follow-up for patients was less than 7 years, 74% of the deaths were a result of causes other than HL.1  Other retrospective reviews from the United States, as well as Europe, in which patients were treated either with limited or more extensive irradiation, also failed to show benefit from the extended treatment (Table 1).32-35  However, caution should be taken with attempts to compare results of different studies, given differences in patient selection criteria, staging studies employed, duration of follow-up, and so on.

Most groups that employ primary RT in early-stage disease use the IFRT concept to define radiation fields. The strict definition of IFRT is that the fields conform to the boundaries of the lymphoid regions, as defined for the Ann Arbor classification system.36  In some instances, this definition was modified to exclude the high cervical lymph nodes if only the supraclavicular nodes were involved. More recently, the European Organization for Research and Treatment of Cancer advocated for even more restricted fields, termed “involved-node” radiotherapy (INRT),37  and the International Lymphoma Radiation Oncology Group has defined “involved-site” radiotherapy (ISRT).38  Using the ISRT concept, radiation fields for primary management of NLPHL would include involved nodes, defined by CT and PET, with reasonable extension (∼5 cm) after the lymphatic drainage proximally and ∼2 to 5 cm distally, depending on regions involved.

RT dose is another variable that has been evaluated only retrospectively. Nearly all series have used doses in the 30- to 40-Gy range, with little evidence of difference in outcome.35  The National Comprehensive Cancer Network (NCCN) recommends a dose of 30 to 36 Gy, and the European Society for Medical Oncology (ESMO) a dose of 30 Gy.39,40  Following up on studies in follicular lymphomas that report high response rates with doses as low as 4 Gy for palliative therapy, a single study of a 4-Gy dose has been reported in NLPHL, yielding a 3-year PFS of only 63%. These results are unacceptably poor compared with conventional dose therapy and, hence, are not recommended.41 

Surgery alone

Observation after surgical resection has been evaluated primarily in pediatric patients. The European Network Group on Pediatric Hodgkin Lymphoma reported on 58 children treated with resection only.42  A total of 51 children (84%) achieved a complete response (CR) after excisional biopsy. The PFS was 57% at 50 months for the entire group, and 67% at 26 months for patients in CR after surgery. All patients with incomplete resection eventually relapsed at a median of 17 months with no effect on OS (100%), suggesting an excellent salvage rate in these patients.

A prospective study by the Children’s Oncology Group reported on 52 patients observed after completely resected stage IA disease. At a median follow-up of 26 months, the 2-year event-free survival and OS were 88% and 100%, respectively.43  In 1 adult study, for which details of patient characteristics are lacking, the 10-year PFS was 41%.28  Collectively, these data suggest that observation might be an option in carefully selected patients with stage I disease in CR after surgical resection, but this policy cannot be recommended routinely in clinical practice, as most of these patients ultimately develop disease progression.

Combined modality therapy

During the last 2 decades, although the standard of care for early-stage cHL has become CMT, there is a paucity of studies comparing CMT with RT alone in early-stage NLPHL.

Retrospective studies from the MD Anderson Cancer Center (MDACC), the GHSG, and the Harvard study groups failed to show improvement in outcome with CMT compared with RT alone (Table 1).32,34,44  In contrast, a retrospective study from the BCCA comparing the outcome of 35 patients treated with RT alone with 51 patients treated with chemotherapy (usually ABVD [adriamycin, bleomycin, vinblastine, and dacarbazine]) with or without RT showed an improvement at 10 years in both PFS and OS, using a chemotherapy-based approach.45  As with all the retrospective studies noted earlier, cautious interpretation is required because of different selection criteria, variable staging procedures, availability of supportive care, and substantial differences in duration of follow-up for the different therapies.

Chemotherapy alone

There are few data regarding use of chemotherapy alone in adults with early-stage NLPHL (Table 1). Limited pediatric data have used cyclophosphamide, vinblastine, and prednisone and cyclophosphamide, vincristine, procarbazine, prednisone (COPP)/ABVD.43,46,47  Although survival was excellent, treatment failure was common. In a retrospective report from the BCCA, no relapses were identified (median follow-up, ∼5 years) in a subset of 14 patients treated with ABVD alone if an interim PET scan were normal.45  Although these BCCA results are provocative, it is important to note that the follow-up is rather brief for this disease, which is often associated with late relapse.

Rituximab in early-stage disease

Because consistent CD20 expression represents a hallmark of NLPHL, prospective studies have evaluated the role of the anti-CD20 antibody rituximab. In a GHSG study, 28 patients with stage IA disease without clinical risk factors received 4 weekly standard doses (375 mg/m2) of rituximab. The overall response rate (ORR) was 100%. However, at a median follow-up of 43 months, 25% of patients relapsed, which is a higher percentage than would be expected after RT alone.48  In a study from Stanford, 13 previously untreated patients with early-stage NLPHL received rituximab as single agent. Although the response rate was 100%, the relapse rate was similar to that seen by the GHSG.29  Cumulatively, these studies suggest that although rituximab as a single agent may have a role in the management of NLPHL, it cannot be recommended as a first-line therapy for patients with newly diagnosed, early-stage disease.

Recommendations for early-stage disease

Although some centers advocate the use of CMT for patients with stage IA disease, both the NCCN and ESMO recommend IFRT alone.39,40  For stage IIA disease, IFRT remains the recommendation from NCCN, whereas the ESMO guidelines recommend CMT, which is analogous to cHL. Neither organization recommends the use of rituximab, either alone or in combination (Table 3).

Table 3

NCCN and ESMO guidelines for NLPHL

Stage
GuidelineIA, no risk factors40 IBIIAIIBIII/IV AIII/IV B
NCCN guidelines, version 2.201339  (all category 2A unless otherwise indicated) Observe* or ISRT CHT ± rituximab ± ISRT Observe or ISRT CHT ± rituximab ± ISRT CHT ± rituximab ± RT or observation or local RT CHT ± rituximab ± RT 
ESMO40  IFRT CHT ± IFRT CHT ± IFRT CHT ± IFRT CHT CHT 
Stage
GuidelineIA, no risk factors40 IBIIAIIBIII/IV AIII/IV B
NCCN guidelines, version 2.201339  (all category 2A unless otherwise indicated) Observe* or ISRT CHT ± rituximab ± ISRT Observe or ISRT CHT ± rituximab ± ISRT CHT ± rituximab ± RT or observation or local RT CHT ± rituximab ± RT 
ESMO40  IFRT CHT ± IFRT CHT ± IFRT CHT ± IFRT CHT CHT 

CHT, chemotherapy (for details see reference).

*

Option for completely excised solitary lymph node

Category 2B

Palliation only

At Stanford, patients with clinical stage I to IIA are managed primarily with RT. Because bone marrow involvement is rare, a biopsy is warranted only in patients with advanced-stage disease, B symptoms, or cytopenias. Patients undergo a thorough imaging evaluation, including a diagnostic CT scan and an FDG-PET scan. To delineate the radiation fields, findings from the physical exam are integrated with the imaging results to define the gross tumor volume, which includes palpably enlarged nodes, enlarged nodes on CT, and PET-positive normal size nodes. The clinical target volume is defined by expanding the gross tumor volume ∼1 cm in axial dimensions and 2.5 cm proximally and distally, following the normal anatomy of the lymph node regions but not including normal structures such as muscle and bone. An additional 0.5-cm expansion is incorporated to define the planning target volume. This results in what has been designated ISRT by the International Lymphoma Radiation Oncology Group,38  a definition that is generally less than classical “involved-field irradiation” and greater than INRT. This is warranted, as the INRT definition was developed primarily for treatment with CMT and, therefore, is too restrictive for treatment with RT alone. The dose we use is 30 to 36 Gy in 1.5- to 1.8-Gy fractions. The higher dose range is restricted to sites of bulkier disease or disease that regresses very slowly. We do not incorporate chemotherapy or rituximab in the routine management of patients with stage IA to IIA disease.

Stage IB to IIB and stage I to II disease with more than 3 sites of involvement or bulky (>10 cm) disease are uncommon presentations for NLPHL and are treated according to protocols used for cHL with similar outcomes (Table 3). Rituximab may be included as a component of systemic therapy, although evidence for an improved outcome is lacking.

Treatment of advanced stages

Advanced-stage presentations of NLPHL occur in 20% to 25% patients. Careful consideration needs to be given to clinical history and sites of disease, as there may be occult transformation.20,29 

Chemotherapy is the mainstay of treatment of patients with advanced stage with regimens similar to those used for cHL (Table 2). Most data are retrospective and include studies conducted across several decades. The BCCA reported a matched control outcome analysis of patients with NLPHL (n = 42) or cHL (n = 82) treated with ABVD or ABVD-like chemotherapy.49  At 15 years, there was a trend toward superior PFS for cHL compared with LPHL (72% vs 44%; P = .096). The largest series of patients with advanced disease is from the GHSG, comparing outcomes of 83 patients with NLPHL with outcomes of 3083 patients with cHL included in prospective trials.19  There were no significant differences in 50-month FFTF rates for patients with NLPHL or cHL (77% and 75%, respectively; P = .46). Of note, chemotherapy used in the GHSG trials included COPP, COPP/ABVD, COPP/ABV (doxorubicin, bleomycin, and vincristine)/IMEP (iphosphamide, methotrexate, etoposide, and prednisone), and BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) (baseline and escalated) that contain significantly higher doses of alkylating agents than ABVD.

The idea that alkylator-based therapy may have an advantage over non-alkylator-based regimens in NLPHL is also supported by a retrospective analysis from the Cancer and Leukemia Group B of 37 patients with advanced NLPHL.50  Patients were treated with MOPP (mechlorethamine, vincristine, procarbazine, prednisone), MOPP/ABVD, or ABVD/EVA (etoposide, vinblastine, adriamycin). The relapse rate was 75% among patients treated with ABVD/EVA but only 32% in patients treated with MOPP or MOPP/ABVD, suggesting that alkylator-based chemotherapy may be more effective for the treatment of advanced-stage NLPHL. There are also retrospective data on the use of RCHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) in advanced NLPHL from the MDACC.51  At a median follow-up of 42 months, no relapse or transformation was seen among 15 patients, again supporting the role of alkylator-based therapy.

The use of rituximab as single agent has also been evaluated in front-line therapy in advanced-stage disease. Despite a high response rate, relapses are common, limiting this option to a palliative setting.29,52  RT may also serve a palliative benefit in advanced disease.

Recommendations for advanced-stage disease

The NCCN guidelines include a broad range of options that depend on the goals of therapy.39  Curative management generally includes both chemotherapy and rituximab, whereas palliative management includes observation or local radiation. The ESMO guidelines consider management to be the same as for cHL (Table 3).40 

At Stanford, patients with advanced disease are treated with curative intent. Given the universal expression of CD20, our usual first-line approach incorporates rituximab with regimens used for cHL. For patients who present with B symptoms or abdominal involvement, scenarios in which there may be occult transformation, we favor using RCHOP for 6 cycles.51 

Treatment of relapsed NLPHL

Patients with NLPHL, in comparison with those with cHL, have an increased risk for late relapse for which standard treatment is not well-defined.19,28,53  A subset may develop chronic relapsing disease, with new manifestations of disease appearing during a period of many years, often with limited extent in peripheral nodes. Palliative management is appropriate for this group. Therapy decisions depend on multiple factors, including prior therapy response duration, treatment intent, and comorbidities. Biopsy documentation of clinical relapse is essential to exclude PTGC or transformation to an aggressive B-cell lymphoma.

Unlike relapsed cHL, data on high-dose chemotherapy followed by ASCT for relapsed NLPHL are scarce and largely based on retrospective series. The MDACC reported on 26 patients with relapsed NLPHL treated with high-dose chemotherapy and ASCT between 1990 and 2008. With a median follow-up of 50 months, the 5-year OS and EFS were 76% and 69%, respectively.54  In another study, outcomes with ASCT of 19 patients with relapsed or refractory NLPHL were compared with those of 299 patients with relapsed/refractory cHL. The 5-year PFS and OS were similar, at 50% vs 39% (P = .30) and 56% vs 53% (P = .36), respectively.55 

Other treatment modalities, such as localized RT, conventional chemotherapy, or CMT, may also be options, although no large series on these strategies has been published to date. Case reports with rituximab plus ifosfamide, carboplatin, and etoposide (RICE) suggest a high ORR, but durability is unknown.56 

Prospective studies have evaluated the role of rituximab in the relapsed setting. At Stanford, a phase 2 study included 18 patients with relapsed NLPHL treated with 4 weekly doses of rituximab (R alone) at standard doses (n = 11) or R + R maintenance (MR) for 2 years (n = 7). At the end of induction therapy with R, ORR was 100% (CR, 78%).29  Although the estimated 5-year PFS of the patients treated with R + MR was 71.4% (95% CI, 44.7-100), it was not statistically significantly superior to R alone (5 year PFS, 36.4%; 95% CI, 16.6-79.5), likely as a result of small patient numbers. The median OS was not reached for either group. In a study conducted by the GHSG, 15 patients with relapsed NLPHL received 4 weekly standard doses of rituximab. All but 1 patient responded to treatment. After a median observation of 63 months, the median time to progression was 33 months, and median OS not reached.57  Cumulatively, these data suggest that although treatment with rituximab alone results in an excellent initial response, therapy is not curative, and a continuous pattern of relapse is seen, despite MR. However, given the excellent tolerability of rituximab, monotherapy use in the relapsed setting is a reasonable consideration.

Recommendations for relapsed disease

The NCCN guidelines emphasize the importance of rebiopsy. Patients who relapse with transformation should be managed according to algorithms for DLBCL. Symptomatic patients with a documented relapse of NLPHL may be treated with any combination of chemotherapy, rituximab, or RT, depending on the extent of disease and nature of the symptoms. Asymptomatic patients may also be observed.39 

At Stanford, we follow NCCN guidelines, and selection of salvage therapy depends on treatment intent and disease burden. For localized relapse, consideration is first given to local radiotherapy. For asymptomatic patients with low tumor burden, we often observe without therapy and use guidelines similar to those used in follicular lymphoma to determine treatment indications.58  Single-agent rituximab is often the first choice considered. For patients who have significant tumor burden and are transplant-eligible, we favor using a standard salvage regimen (ie, RICE) for 2 to 3 cycles. For transplant-ineligible patients, palliation with single-agent rituximab is preferred.

Conclusions

NLPHL is rare, with few prospective trials to guide therapy. RT continues to play an integral role in stage I to II disease, as does chemotherapy in advanced stages. The optimal chemotherapy is debatable, and some data suggest that including an alkylating agent may improve efficacy. Although the results with single-agent rituximab in the front-line setting are inferior to conventional therapy, rituximab is a reasonable choice for patients with relapsed disease. The inherent risk of developing an aggressive B-cell lymphoma underscores the importance of long-term follow-up, as well as rebiopsy at relapse. Randomized trials are likely not feasible because of the rarity of NLPHL; however, strategies to consider testing include “watch and wait” for selected patients, such as young children with limited asymptomatic disease or individuals with totally excised solitary nodal involvement, and combinations of targeted therapy, such as rituximab or other anti-CD20 monoclonal antibodies with conventional therapy. The ultimate goal must be maintenance of excellent PFS and minimization of risk for late effects.

Acknowledgments

The authors thank Sarah Daadi for assistance in manuscript preparation and editing.

Authorship

Contribution: R.H.A. and R.T.H. wrote and edited the manuscript.

Conflict-of-interest disclosure: R.H.A. receives research support from Genentech and participates as an unpaid member of their Hematology National Advisory Board. R.T.H. and R.H.A. have received consultancy fees from Clarient Inc.

Correspondence: Ranjana H. Advani, Stanford University Medical Center, 875 Blake Wilbur Dr, CC-2338, Stanford, CA 94305; e-mail: radvani@stanford.edu.

References

References
1
Diehl
 
V
Sextro
 
M
Franklin
 
J
, et al. 
Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin’s Disease.
J Clin Oncol
1999
, vol. 
17
 
3
(pg. 
776
-
783
)
2
Stein
 
H
 
Hodgkin lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008
3
Harris
 
NL
Shades of gray between large B-cell lymphomas and Hodgkin lymphomas: differential diagnosis and biological implications.
Mod Pathol
2013
, vol. 
26
 
Suppl 1
(pg. 
S57
-
S70
)
4
Mason
 
DY
Banks
 
PM
Chan
 
J
, et al. 
Nodular lymphocyte predominance Hodgkin’s disease. A distinct clinicopathological entity.
Am J Surg Pathol
1994
, vol. 
18
 
5
(pg. 
526
-
530
)
5
Carbone
 
A
Spina
 
M
Gloghini
 
A
Ponzoni
 
M
Doglioni
 
C
Tirelli
 
U
Nodular lymphocyte predominant Hodgkin lymphoma with non-invasive or early invasive growth pattern suggests an early step of the disease with a highly favorable outcome
Am J Hematol
2013
, vol. 
88
 
2
(pg. 
161
-
162
)
6
Boudová
 
L
Torlakovic
 
E
Delabie
 
J
, et al. 
Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma.
Blood
2003
, vol. 
102
 
10
(pg. 
3753
-
3758
)
7
Küppers
 
R
Rajewsky
 
K
Zhao
 
M
, et al. 
Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development.
Proc Natl Acad Sci USA
1994
, vol. 
91
 
23
(pg. 
10962
-
10966
)
8
Delabie
 
J
Tierens
 
A
Wu
 
G
Weisenburger
 
DD
Chan
 
WC
Lymphocyte predominance Hodgkin’s disease: lineage and clonality determination using a single-cell assay.
Blood
1994
, vol. 
84
 
10
(pg. 
3291
-
3298
)
9
Marafioti
 
T
Hummel
 
M
Anagnostopoulos
 
I
, et al. 
Origin of nodular lymphocyte-predominant Hodgkin’s disease from a clonal expansion of highly mutated germinal-center B cells [see comments].
N Engl J Med
1997
, vol. 
337
 
7
(pg. 
453
-
458
)
10
Schumacher
 
MA
Schmitz
 
R
Brune
 
V
, et al. 
Mutations in the genes coding for the NF-κB regulating factors IκBα and A20 are uncommon in nodular lymphocyte-predominant Hodgkin’s lymphoma.
Haematologica
2010
, vol. 
95
 
1
(pg. 
153
-
157
)
11
Saarinen
 
S
Aavikko
 
M
Aittomäki
 
K
, et al. 
Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma.
Blood
2011
, vol. 
118
 
3
(pg. 
493
-
498
)
12
Anagnostopoulos
 
I
Hansmann
 
ML
Franssila
 
K
, et al. 
European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes.
Blood
2000
, vol. 
96
 
5
(pg. 
1889
-
1899
)
13
Stein
 
H
Delsol
 
G
Pileri
 
SA
Jaffe
 
ES
Harris
 
NL
Stein
 
H
Vardiman
 
JW
Hodgkin lymphoma.
 
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer Press; 2001:237-253
14
Venkataraman
 
G
Raffeld
 
M
Pittaluga
 
S
Jaffe
 
ES
CD15-expressing nodular lymphocyte-predominant Hodgkin lymphoma.
Histopathology
2011
, vol. 
58
 
5
(pg. 
803
-
805
)
15
Greiner
 
TC
Gascoyne
 
RD
Anderson
 
ME
, et al. 
Nodular lymphocyte-predominant Hodgkin’s disease associated with large-cell lymphoma: analysis of Ig gene rearrangements by V-J polymerase chain reaction.
Blood
1996
, vol. 
88
 
2
(pg. 
657
-
666
)
16
Wickert
 
RS
Weisenburger
 
DD
Tierens
 
A
Greiner
 
TC
Chan
 
WC
Clonal relationship between lymphocytic predominance Hodgkin’s disease and concurrent or subsequent large-cell lymphoma of B lineage.
Blood
1995
, vol. 
86
 
6
(pg. 
2312
-
2320
)
17
Shankar
 
A
Daw
 
S
Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents—a comprehensive review of biology, clinical course and treatment options.
Br J Haematol
2012
, vol. 
159
 
3
(pg. 
288
-
298
)
18
Saarinen
 
S
Pukkala
 
E
Vahteristo
 
P
Mäkinen
 
MJ
Franssila
 
K
Aaltonen
 
LA
High familial risk in nodular lymphocyte-predominant Hodgkin lymphoma.
J Clin Oncol
2013
, vol. 
31
 
7
(pg. 
938
-
943
)
19
Nogová
 
L
Reineke
 
T
Brillant
 
C
, et al. 
German Hodgkin Study Group
Lymphocyte-predominant and classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin Study Group.
J Clin Oncol
2008
, vol. 
26
 
3
(pg. 
434
-
439
)
20
Al-Mansour
 
M
Connors
 
JM
Gascoyne
 
RD
Skinnider
 
B
Savage
 
KJ
Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin’s lymphoma.
J Clin Oncol
2010
, vol. 
28
 
5
(pg. 
793
-
799
)
21
Hutchings
 
M
Loft
 
A
Hansen
 
M
, et al. 
Position emission tomography with or without computed tomography in the primary staging of Hodgkin’s lymphoma.
Haematologica
2006
, vol. 
91
 
4
(pg. 
482
-
489
)
22
Ansquer
 
C
Hervouët
 
T
Devillers
 
A
, et al. 
18-F FDG-PET in the staging of lymphocyte-predominant Hodgkin’s disease.
Haematologica
2008
, vol. 
93
 
1
(pg. 
128
-
131
)
23
Feugier
 
P
Labouyrie
 
E
Djeridane
 
M
, et al. 
Comparison of initial characteristics and long-term outcome of patients with lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma at clinical stages IA and IIA prospectively treated by brief anthracycline-based chemotherapies plus extended high-dose irradiation.
Blood
2004
, vol. 
104
 
9
(pg. 
2675
-
2681
)
24
Jackson
 
H
Parker
 
F
Hodgkin's Disease and Allied Disorders
1947
New York
Oxford University Press
25
Porrata
 
LF
Ristow
 
K
Habermann
 
TM
, et al. 
Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte-predominant Hodgkin lymphoma.
Br J Haematol
2012
, vol. 
157
 
3
(pg. 
321
-
330
)
26
Rüdiger
 
T
Gascoyne
 
RD
Jaffe
 
ES
, et al. 
Workshop on the relationship between nodular lymphocyte predominant Hodgkin’s lymphoma and T cell/histiocyte-rich B cell lymphoma.
Ann Oncol
2002
, vol. 
13
 
Suppl 1
(pg. 
44
-
51
)
27
Huang
 
JZ
Weisenburger
 
DD
Vose
 
JM
, et al. 
Diffuse large B-cell lymphoma arising in nodular lymphocyte predominant Hodgkin lymphoma: a report of 21 cases from the Nebraska Lymphoma Study Group.
Leuk Lymphoma
2004
, vol. 
45
 
8
(pg. 
1551
-
1557
)
28
Biasoli
 
I
Stamatoullas
 
A
Meignin
 
V
, et al. 
Nodular, lymphocyte-predominant Hodgkin lymphoma: a long-term study and analysis of transformation to diffuse large B-cell lymphoma in a cohort of 164 patients from the Adult Lymphoma Study Group.
Cancer
2010
, vol. 
116
 
3
(pg. 
631
-
639
)
29
Advani
 
RH
Horning
 
SJ
Hoppe
 
RT
, et al. 
Mature results of a phase II study of rituximab therapy for nodular lymphocyte predominant Hodgkin lymphoma.
J Clin Oncol
2013
 
In press
30
Russell
 
KJ
Hoppe
 
RT
Colby
 
TV
Burns
 
BF
Cox
 
RS
Kaplan
 
HS
Lymphocyte predominant Hodgkin’s disease: clinical presentation and results of treatment.
Radiother Oncol
1984
, vol. 
1
 
3
(pg. 
197
-
205
)
31
Engert
 
A
Plütschow
 
A
Eich
 
HT
, et al. 
Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma.
N Engl J Med
2010
, vol. 
363
 
7
(pg. 
640
-
652
)
32
Nogová
 
L
Reineke
 
T
Eich
 
HT
, et al. 
Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG).
Ann Oncol
2005
, vol. 
16
 
10
(pg. 
1683
-
1687
)
33
Schlembach
 
PJ
Wilder
 
RB
Jones
 
D
, et al. 
Radiotherapy alone for lymphocyte-predominant Hodgkin’s disease.
Cancer J
2002
, vol. 
8
 
5
(pg. 
377
-
383
)
34
Chen
 
RC
Chin
 
MS
Ng
 
AK
, et al. 
Early-stage, lymphocyte-predominant Hodgkin’s lymphoma: patient outcomes from a large, single-institution series with long follow-up.
J Clin Oncol
2010
, vol. 
28
 
1
(pg. 
136
-
141
)
35
Wirth
 
A
Yuen
 
K
Barton
 
M
, et al. 
Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australasian Radiation Oncology Lymphoma Group.
Cancer
2005
, vol. 
104
 
6
(pg. 
1221
-
1229
)
36
Kaplan
 
HS
Rosenberg
 
SA
The treatment of Hodgkin’s disease.
Med Clin North Am
1966
, vol. 
50
 
6
(pg. 
1591
-
1610
)
37
Girinsky
 
T
van der Maazen
 
R
Specht
 
L
, et al. 
Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines.
Radiother Oncol
2006
, vol. 
79
 
3
(pg. 
270
-
277
)
38
Specht
 
L
Yahalom
 
J
Illidge
 
T
et al. 
Modern radiotherapy for Hodgkin lymphoma: field and dose guidelines from the International Lymphoma Radiation Oncology Group (ILROG).
Int J Radiat Oncol Biol Phys
 
[published online ahead of print June 18, 2013]. doi: 10.1016/j.ijrobp.2013.05.005
39
National Comprehensive Cancer Network Guidelines Version 2.2013. Hodgkin Lymphoma. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed May 24, 2013
40
Eichenauer
 
DA
Engert
 
A
Dreyling
 
M
ESMO Guidelines Working Group
Hodgkin’s lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol
2011
, vol. 
22
 
Suppl 6
(pg. 
vi55
-
vi58
)
41
Haas
 
RL
Girinsky
 
T
Aleman
 
BM
Henry-Amar
 
M
de Boer
 
JP
de Jong
 
D
Low-dose involved-field radiotherapy as alternative treatment of nodular lymphocyte predominance Hodgkin’s lymphoma.
Int J Radiat Oncol Biol Phys
2009
, vol. 
74
 
4
(pg. 
1199
-
1202
)
42
Mauz-Körholz
 
C
Gorde-Grosjean
 
S
Hasenclever
 
D
, et al. 
Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma.
Cancer
2007
, vol. 
110
 
1
(pg. 
179
-
185
)
43
Appel
 
B
Ehrlich
 
P
Chen
 
L
, et al. 
 
Treatment of pediatric stage IA lymphocyte-predominant Hodgkin lymphoma with surgical resection alone: A report from the Children's Oncology Group. ASCO Meeting Abstracts. 2012;30(15_suppl):9524
44
Wilder
 
RB
Schlembach
 
PJ
Jones
 
D
, et al. 
 
European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte very favorable and favorable, lymphocyte-predominant Hodgkin disease. Cancer. 2002;94(6):1731-1738
45
Savage
 
KJ
Skinnider
 
B
Al-Mansour
 
M
Sehn
 
LH
Gascoyne
 
RD
Connors
 
JM
Treating limited-stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome.
Blood
2011
, vol. 
118
 
17
(pg. 
4585
-
4590
)
46
Shankar
 
A
Hall
 
GW
Gorde-Grosjean
 
S
, et al. 
Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin’s lymphoma - an Anglo-French collaborative report.
Eur J Cancer
2012
, vol. 
48
 
11
(pg. 
1700
-
1706
)
47
Wolden
 
SL
Chen
 
L
Kelly
 
KM
, et al. 
Long-term results of CCG 5942: a randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin’s lymphoma—a report from the Children’s Oncology Group.
J Clin Oncol
2012
, vol. 
30
 
26
(pg. 
3174
-
3180
)
48
Eichenauer
 
DA
Fuchs
 
M
Pluetschow
 
A
, et al. 
Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group.
Blood
2011
, vol. 
118
 
16
(pg. 
4363
-
4365
)
49
Xing
 
KH
Connors
 
JM
Al-Mansour
 
M
Gascoyne
 
RD
Skinnider
 
B
Savage
 
KJ
 
The outcome of advanced stage nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) compared to classical Hodgkin's lymphoma (CHL): a matched pair analysis. ASH Annual Meeting Abstracts. 2012;120(21):1531
50
Canellos
 
GP
Mauch
 
P
What is the appropriate systemic chemotherapy for lymphocyte-predominant Hodgkin’s lymphoma?
J Clin Oncol
2010
, vol. 
28
 
1
pg. 
e8
 
51
Fanale
 
MA
Lai
 
C-M
McLaughlin
 
P
, et al. 
 
Outcomes of Nodular Lymphocyte Predominant Hodgkin's Lymphoma (NLPHL) Patients Treated with R-CHOP. ASH Annual Meeting Abstracts. 2010;116(21):2812
52
Ekstrand
 
BC
Lucas
 
JB
Horwitz
 
SM
, et al. 
Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial.
Blood
2003
, vol. 
101
 
11
(pg. 
4285
-
4289
)
53
Chera
 
BS
Olivier
 
K
Morris
 
CG
Lynch
 
JW
Mendenhall
 
NP
Clinical presentation and outcomes of lymphocyte-predominant Hodgkin disease at the University of Florida.
Am J Clin Oncol
2007
, vol. 
30
 
6
(pg. 
601
-
606
)
54
Karuturi
 
M
Hosing
 
C
Fanale
 
M
, et al. 
High-dose chemotherapy and autologous stem cell transplantation for nodular lymphocyte-predominant Hodgkin lymphoma.
Biol Blood Marrow Transplant
2013
, vol. 
19
 
6
(pg. 
991
-
994
)
55
Bierman
 
P
Naushad
 
H
Loberiza
 
F
, et al. 
High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) for lymphocyte predominant Hodgkin’s disease [abstract].
Blood
2006
, vol. 
108
 
11
 
Abstract 3061
56
Park
 
HC
Jung
 
SH
Ahn
 
JS
, et al. 
Rituximab plus ifosfamide, carboplatin and etoposide for T-cell/histiocyte-rich B-cell lymphoma arising in nodular lymphocyte-predominant Hodgkin’s lymphoma.
Case Rep Oncol
2012
, vol. 
5
 
2
(pg. 
413
-
419
)
57
Schulz
 
H
Rehwald
 
U
Morschhauser
 
F
, et al. 
Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG).
Blood
2008
, vol. 
111
 
1
(pg. 
109
-
111
)
58
Salles
 
G
Mounier
 
N
de Guibert
 
S
, et al. 
Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study.
Blood
2008
, vol. 
112
 
13
(pg. 
4824
-
4831
)