International Journal of

Radiation Oncology
biology

physics

www.redjournal.org

Clinical Investigation

Management of Nodular Lymphocyte

Predominant Hodgkin Lymphoma in the
Modern Era
Martin T. King, MD, PhD,* Sarah S. Donaldson, MD,*
Michael P. Link, MD,y Yasodha Natkunam, MD, PhD,z
Ranjana H. Advani, MD,x and Richard T. Hoppe, MD*
Departments of *Radiation Oncology, yPediatrics, zPathology, and xMedicine, Stanford Cancer
Institute, Stanford, California
Received Oct 21, 2014, and in revised form Jan 15, 2015. Accepted for publication Feb 2, 2015.

Summary
A single-institution analysis
of nodular lymphocyte predominant Hodgkin lymphoma between 1996 and
2013 was conducted. For
limited-stage (I-II) disease,
response-adaptive therapy, in
which radiation therapy (RT)
dose was reduced or eliminated after initial chemotherapy, demonstrated
outcomes comparable with
those of RT alone. Rituximab
monotherapy demonstrated
inferior outcomes for limited
disease and a high relapse
rate for advanced-stage (IIIIV) disease.

Purpose: To analyze treatment outcomes for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) at a single institution.
Patients and Methods: Patients with newly diagnosed NLPHL between 1996 and
2013 were reviewed retrospectively. Patients treated before 1996 were excluded
because the majority received extended field radiation therapy (RT) alone.
Results: Fifty-five patients (22  21 years old) were identified. The median follow-up
time was 6.8 years. Among 37 patients with limited-stage (I-II) disease, treatments
included involved field RT at a median dose of 36 Gy (nZ9), rituximab monotherapy
(nZ9), observation (nZ3), and response-adaptive therapy (nZ16), in which the RT
dose was reduced from 25.5 Gy to 15 Gy or was eliminated based on interim imaging
after chemotherapy. The 5-year progression-free survival (PFS) was 76.4% (95% confidence interval [CI], 63.1-92.4). Nine patients experienced progression, including 5
receiving rituximab, 2 undergoing observation, and 2 receiving response-adaptive therapy. Rituximab was associated with an inferior PFS compared with RT alone (PZ.02).
The difference in PFS between response-adaptive therapy and RT alone was not statistically significant (PZ.39). Among 18 patients with advanced-stage (III-IV) disease, treatments included chemotherapy alone (nZ3), combined modality therapy
(CMT) (nZ2), response-adaptive therapy (nZ2), rituximab (nZ7), and observation
(nZ4). The 5-year PFS was 29.9% (CI, 13.3-67.4). Twelve patients experienced progression, including 1 receiving chemotherapy, 1 receiving CMT, 6 receiving rituximab, and 4 undergoing observation. There was no significant PFS difference
between rituximab and non-rituximab therapies (PZ.19) within the caveat of small
sample sizes. In the entire cohort, 9 patients (3 with limited disease, 6 with advanced

Reprint requests to: Martin King, MD, PhD, 875 Blake Wilbur Drive,
Stanford, CA 94305. Tel: (650)725-4782; E-mail: mking1@stanford.edu
Presented in part at the 56th Annual Meeting of the American Society
for Radiation Oncology in San Francisco, California, September 1417, 2014.
Int J Radiation Oncol Biol Phys, Vol. 92, No. 1, pp. 67e75, 2015
0360-3016/$ - see front matter 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2015.02.001

Conflict of interest: none.

Supplementary material for this article can be found online at
www.redjournal.org.

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International Journal of Radiation Oncology  Biology  Physics

King et al.

disease) experienced large cell transformation (LCT). Seven patients died; of those, 5
died with LCT.
Conclusions: For limited disease, response-adaptive therapy demonstrated comparable outcomes with RT alone. Rituximab monotherapy resulted in inferior outcomes
for limited disease and a high relapse rate for advanced disease. 2015 Elsevier
Inc. All rights reserved.

Introduction
Nodular lymphocyte predominant Hodgkin lymphoma
(NLPHL) is an uncommon subtype of lymphoma, with
characteristics that differentiate it from classical Hodgkin
lymphoma (CHL). Whereas CHL is defined by the presence
of CD30 and CD15 Hodgkin/Reed-Sternberg cells, the
large atypical cells of NLPHL are uniformly CD20 (1).
Compared with CHL, NLPHL has a more indolent clinical
course and carries a more favorable prognosis (2). However, unlike CHL, NLPHL carries the risk of late relapses
(3) and large cell transformation (LCT) (4).
In the era when radiation therapy (RT) was used as the
sole modality for treating limited-stage (I-II) NHLPL,
patient deaths were more often related to treatment (eg,
secondary cancers and cardiovascular disease) rather than
to disease progression (5, 6). Recent investigations have
focused on the reduction of late treatment toxicities through
RT field reduction (6, 7) and dose de-escalation. In the
pediatric population, response-adaptive therapy, in which
RT dose is reduced (8) or eliminated (9) based on interim
imaging response after chemotherapy, has produced
promising results. In the adult population, rituximab (antiCD20) monoclonal antibody therapy has been evaluated for
patients with newly diagnosed NLPHL, including those
with limited disease (10, 11). Other strategies that have
been reported include surgery alone (12), chemotherapy
alone (13, 14), combined modality therapy (CMT) (15), and
low-dose involved field RT (16). At our institution, we have
used standard RT alone, we have evaluated responseadaptive therapy for pediatric patients, and we have conducted studies to assess rituximab monotherapy.
The goals of this single-institution retrospective study
were as follows: first, to report clinical outcomes by stage
(limited vs advanced) and treatment modality and, second,
to clarify the roles of response-adaptive therapy and rituximab monotherapy for limited disease.

Patients and Methods

Patient demographics
We conducted an institutional review boarddapproved
retrospective review of all patients with newly diagnosed
NLPHL who were treated at our institution from 1996 to
2013. We included pediatric (age 21) and adult (age >21)
patients, and we excluded those treated before 1996

because the majority received RT with older extended field

techniques (17). Patients who presented with relapsed
NLPHL and those who had LCT at first presentation were
also excluded. The diagnoses of all patients were reconfirmed by a single expert hematopathologist based on
morphology and immunohistochemical profile (typically
CD20, CD15, CD30) as defined by the World Health
Organization 2008 classification (18).
For each patient, we collected relevant demographic,
staging, treatment, and follow-up information. Potential
adverse factors that were specifically evaluated included
presence of B symptoms, extranodal disease, 3 involved
sites, infradiaphragmatic disease, lymphadenopathy
measuring >5 cm, elevated sedimentation rate, and variant
histology (19, 20). Gross total resection was assigned to
patients with stage IA disease who had no clinical or
radiographic evidence of residual tumor after excisional
biopsy. Treatment response was designated as complete
response (CR) or partial response (PR) based on protocol
specifications if patients were analyzed prospectively. For
patients who were not treated on protocols, response was
assessed based on reports from era-dependent imaging
modalities (ie, computed tomography [CT] and positron
emission tomography [PET]) and the clinical judgment
from the treating physician as documented in progress
notes. Radiographic images were not re-reviewed.

Treatment modalities
Treatment modalities included RT alone, chemotherapy
alone, CMT, initial observation, response-adaptive therapy,
and rituximab monotherapy. For CMT, patients were prescribed a course of chemotherapy followed by RT at the
time of consultation. For initial observation, patients had
not begun treatment within 6 months from initial
consultation.
Pediatric patients receiving response-adaptive therapy
were enrolled on, or treated according to, 5 prospective
protocols from the Pediatric Hodgkin Lymphoma Consortium. As shown in Table 1, protocols were defined for
patients with favorable, intermediate, or unfavorable risk
disease. All protocols consisted of 3 components. The
initial component was chemotherapy. Regimens included:
(1) vinblastine, doxorubicin, methotrexate, and prednisone
(VAMP) for 4 total cycles (8, 9); (2) VAMP plus cyclophosphamide, vincristine, and procarbazine (COP) for 6
total cycles (21); and (3) doxorubicin, vinblastine,

Volume 92  Number 1  2015

Table 1

69

Lymphocyte predominant Hodgkin lymphoma

Descriptions of response-adaptive protocols defined for patients with favorable, intermediate, and unfavorable risk disease
Chemotherapy

Protocol
Donaldson et al (8)
Metzger et al (9)
Hudson et al (21)

HOD08 (23)
HOD05 (24)

Risk

Enrollment
period

Eligibility criteria

I-II, MMR <1/3,

no E, <6 cm
Favorable
3/2000-2/2009 I-II, MMR <1/3,
no E, <3 sites
Unfavorable 10/1993-2/2000 III/IV; I/II with bulky LAN
(MMR >1/3 or >6 cm)
or B sx
Favorable 2/2009-Enrolling IA/IIA, MMR <1/3, no E,
<3 sites
Intermediate 7/2006-Closed IB, IIIA, or IA/IIA with
bulky med LAN,
E, 3 sites
Favorable

9/1990-2/2000

Regimen

Radiation therapy

No. of Interim
cycles imaging PR (Gy) CR (Gy)

VAMP

CT

25.5

15

VAMP

PET/CT

25.5

VAMP/COP

CT

25.5

15

PET/CT

25.5

Stanford V 12 wks PET/CT

25.5

15

Stanford V 8 wks

Abbreviations: CR Z complete response; CT Z computed tomography; E Z extranodal site; LAN Z lymphadenopathy; MMR Z mediastinal mass
ratio; PET Z positron emission tomography; PR Z partial response; Stanford V Z doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin,
etoposide, prednisone Sx Z symptom. VAMP Z vinblastine, doxorubicin, methotrexate, prednisone; VAMP/COP Z VAMP/cyclophosphamide,
vincristine, procarbazine.

mechlorethamine, vincristine, bleomycin, etoposide, and

prednisone (Stanford V) (22) for 8 (23) or 12 (24) weeks.
The second component was response assessment with
interim imaging (CT or PET/CT), which occurred after 2
cycles for VAMP and after 8 weeks for Stanford V. The
third component was RT. Patients who achieved a PR
received 25.5 Gy. Those who achieved CR received either
15 Gy or no RT based on the protocol open at the time of
diagnosis. Final results have been reported for the 3 protocols involving VAMP chemotherapy (8, 9, 21). Two
patients, who have completed treatment, are undergoing
surveillance as part of a currently recruiting clinical trial of
reduced duration (8 weeks) Stanford V for favorable disease (23).
For rituximab monotherapy, patients were enrolled on a
phase II clinical trial of 4 weekly doses of rituximab (375 mg/
m2). After protocol amendment, patients were administered 3
additional maintenance courses of weekly rituximab
(4 doses) every 6 months during a 2-year period (11).

Statistical analysis
Progression-free survival (PFS) was defined as the time
from treatment initiation to relapse, progressive disease, or
date of last follow-up visit if none of these events occurred.
For patients designated as undergoing observation, PFS was
assessed from the time of initial consultation to the endpoints listed earlier. Transformation risk was assessed from
the time of initial diagnosis to the time of LCT. Overall
survival (OS) was assessed from the time of diagnosis to
the last date of follow-up visit or death of any cause. PFS,
transformation risk, and OS survival curves were estimated
by Kaplan-Meier analysis. Survival curve comparisons
were performed with the log-rank test. Analysis was

performed with R statistical software version 3.0 (The

R Foundation for Statistical Computing).

Results
Fifty-five patients met the inclusion criteria for this study.
Twenty-two patients were younger than 21 years of age.
The median follow-up time was 6.8 years (range, 0.915.6 years). The percentage of patients with follow-up
times longer than 2 and 5 years were 93% and 67%,
respectively.

Outcomes for limited disease

Thirty-seven patients presented with limited disease. The
number of patients who received RT, response-adaptive
therapy, rituximab monotherapy, and observation were 9,
16, 9, and 3, respectively, as shown in Table 2.
Nine patients were treated with RT alone at a median
dose of 36 Gy (range, 10-44.6 Gy). All patients achieved a
CR. No patient experienced relapse during a median
follow-up time of 5.0 years.
Sixteen patients underwent response-adaptive therapy.
As shown in Table 3, 13 patients had an interim CR to
chemotherapy. Six patients (including 3 with variant histology) received 15 Gy RT, and 7 were treated with
chemotherapy alone. Five patients who received chemotherapy alone had stage IA disease, and 4 of these 5 underwent a gross total resection with no clinical or
radiographic evidence of disease after lymph node excision.
No patient with an initial CR experienced relapse. Three
patients achieved an interim PR after chemotherapy and
received 25.5 Gy of RT. All 3 patients had a CR after RT,

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King et al.

Table 2

Clinical outcomes for limited disease based on treatment modality

Characteristic

Radiation

Response-adaptive

Rituximab

Observation

Total

No.
Age, y
21
Stage
I
II
Baseline factors
B symptoms
Extranodal site
3 or more sites
Infradiaphragmatic*
>5 cm lymphadenopathy
ESR
Elevated
Missing
Variant histology
Gross total resection
Staging PET/CT
Follow-up time, y
Median (range)
Treatment response
Complete response
Partial response
Progression
Biopsy confirmed
Time of progression
5-year PFS (95% CI)
No. at risk
LCT
Time of LCT
Death
Nontransformed NLPHL
Transformed NLPHL
No evidence of NLPHL
Time of death

9
35 (21-51)
1

16
9 (5-16)
16

9
37 (17-62)
1

3
45 (14-58)
1

37
21 (5-62)
19

2
7

6
10

1
0
1
0
0

0
0
3
0
1

0
2
0
1
7

0
0
3
4
11

4
5
2
0
2
1 (0)
0
2
3
0
1
6

1
2

13
24

0
0
1
1 (1)
1

3
0
7
2 (1)
2

1
1
1
1
2

3
6
4
7
26

5.0 (2.5-15.6)

7.5 (3.1-12.8)

7.5 (3.1-13.1)

4.6 (4.0-6.6)

6.6 (2.5-15.6)

9
0
0
0
NA
100
5
0
NA
0
0
0
0
NA

16
0
2
2
4.2 (1.9-6.5)
93.8 (82.6-100)
13
1
6.6
2
0
1
1
7.4 (7.4, 7.5)

6
3
5
1
2.6 (1.6-4.6)
40.0 (17.1-3.8)
2
1
3.2
1
0
1
0
7.5

NA
NA
2
1
1.8 (0.4-3.1)
NA
0
1
6.5
1
0
1
0
6.6

31
3
9
4
(0.4-6.5)
(63.1-2.4)
20
3
(3.2-6.6)
4
0
3
1
(6.6-7.5)

2.6
76.4

6.5

7.4

Abbreviations: CI Z confidence interval; CT Z computed tomography; ESR Z elevated sedimentation rate; LCT Z large cell transformation;
NLPHL Z nodular lymphocyte predominant Hodgkin lymphoma; PET Z positron emission tomography; PFS Z progression-free survival.
* Under infradiaphragmatic, number within parentheses represents number of patients in whom transformed disease developed.

but 2 patients subsequently experienced relapse. One patient with favorable disease (stage IIA disease, mediastinal
mass ratio <1/3, no extranodal site, <6 cm tumor) experienced relapse with LCT outside of the previously irradiated field at 6.6 years, and died of disease progression at
7.5 years. Another patient with unfavorable disease (stage
IIA disease, >6 cm nodal mass) who received 25.5 Gy RT
experienced relapse within the irradiated field at 1.9 years.
He underwent multiple salvage treatments, including reirradiation and 2 stem-cell transplantations, and died of
disseminated histoplasmosis with no evidence of lymphoma at 7.4 years.
Of the 9 patients treated with rituximab, 4 received
additional maintenance therapy. Six patients achieved a
CR. Five patients experienced progression at a median time
of 2.6 years. One patient with limited stage IA disease
experienced LCT at 3.2 years. He received salvage therapy

with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by RT but died of
an unknown cause with active disease at 7.5 years.
For initial observation, 1 patient with infradiaphragmatic
disease and variant histology at diagnosis experienced
progression after 0.4 years and was treated subsequently
with rituximab monotherapy. She then experienced rapidly
progressive disease refractory to multiple chemotherapy
regimens and died of LCT at 6.6 years. Another patient
experienced progression at 3.1 years and underwent
salvage therapy with CMT. A third patient with stage IIA
disease had not experienced progression after 4.6 years of
follow-up.
For the entire limited-stage cohort, 9 of 37 patients
experienced relapse or progression. Three experienced
LCT. The 5-year PFS, transformation risk, and OS were
76.4% (95% CI: 63.1, 92.4), 3.2% (0, 9.2) and 100%,

Volume 92  Number 1  2015

Lymphocyte predominant Hodgkin lymphoma

Table 3 Patients receiving response-adaptive therapy with

limited disease stratified by interim imaging response (CR or
PR) and treatment (chemo or CMT)
Characteristic

CR-Chemo

CR-CMT
15 Gy

PR-CMT
25 Gy

No.
7
6
3
Stage
IA
5
1
0
IIA
2
5
3
Risk
Favorable
7
5
2
Intermediate
0
1
0
Unfavorable
0
0
1
Chemotherapy
VAMP  4 cycles
6
5
1
VAMP/COP  6
0
0
1
cycles
1
0
1
Stanford V  8
weeks
Stanford
0
1
0
V  12 weeks
Gross tumor resection
4
0
0
Follow-up time, y
Median (range)
7.5
8.4
7.4
(3.1-12.8)
(5.1-12.5)
(3.9-7.5)
Outcomes
Relapse
0
0
2
Transform
0
0
1
Death
0
0
2
Abbreviations: Chemo Z chemotherapy; CMT Z combined modality therapy; CR Z complete response; PR Z partial response.
Stanford V Z doxorubicin, vinblastine, mechlorethamine, vincristine,
bleomycin, etoposide, prednisone; VAMP Z vinblastine, doxorubicin,
methotrexate, prednisone; VAMP/COP Z VAMP/cyclophosphamide,
vincristine, procarbazine.
Patients with CR underwent chemo or CMT depending on the
available protocol at diagnosis.

respectively. The estimated 5-year PFS values by treatment

modality were 100% for RT alone, 93.8% (82.6, 100) for
response-adaptive therapy, and 40.0% (17.1, 93.8) for rituximab. Rituximab was associated with an inferior PFS
compared with RT alone (PZ.02), as shown in Figure 1a.
By contrast, there was no significant difference in PFS
between response-adaptive therapy and RT alone (PZ.39).
There was also no significant difference in PFS between
pediatric and adult patients (PZ.38), as shown in Figure E1
(available online at www.redjournal.org).

Outcomes for advanced disease

Eighteen patients presented with advanced disease. Patients
who were treated with chemotherapy alone (nZ3), CMT
(nZ2), and response-adaptive therapy (nZ2), were
aggregated into a non-rituximab category, as shown in
Table 4. The 3 patients treated with chemotherapy alone
received 6 cycles of doxorubicin, bleomycin, vinblastine,
and dacarbazine (ABVD). One patient experienced

71

progression at 2.9 years. Two patients receiving CMT

received chemotherapy (Stanford V for 12 weeks and RCHOP for 6 cycles) followed by 30.6 Gy RT to >5 cm
nodal conglomerates. The patient who received Stanford V
also had variant histology at diagnosis and died with
relapsed disease at 6.8 years. Of 2 patients who received
response-adaptive therapy, 1 patient received 15 Gy for an
interim CR, and the other received 25.5 Gy for an interim
PR. Neither patient experienced relapse. Of note, the median follow-up time of 1.6 years for the non-rituximab
cohort was limited.
All 4 patients undergoing observation experienced progression at 4 years. Two patients were treated with rituximab monotherapy, and the third received an unspecified
rituximab-chemotherapy combination. One patient had
never received salvage therapy at 10.7 years follow-up.
Among the 7 patients who received rituximab monotherapy, 1 received additional maintenance therapy. Six
patients experienced progression at a median time of
2.0 years. All 6 experienced LCT at a median time of
4.5 years. Of note, 5 patients had infradiaphragmatic disease at presentation, 1 patient had variant histology, and 4
patients presented with LCT at first relapse. Two patients
died of LCT at 2.9 and 5.4 years.
For advanced disease, 12 of 18 patients experienced
relapse or progression. Six of the 7 patients who received
rituximab experienced LCT. The 5-year PFS, transformation risk, and OS rates were 29.9% (13.3, 67.4),
21.0% (0, 39.6), and 92.9% (80.3, 100), respectively. The
estimated 5-year PFS values were 66.7% (30, 100) for nonrituximab treatments, 28.6% (8.9, 92.2) for rituximab, and
0% for observation. The difference in PFS between rituximab and non-rituximab treatments (excluding observation)
was not significant (PZ.19).

Outcomes for entire cohort

Among all 55 patients, 21 patients experienced relapse or
progression at a median time of 2.1 years (range, 0.46.7 years). Nine patients (16%) experienced LCT at a median time of 6.5 years (range, 1.2-8.3 years). Seven patients
died at a median time of 6.8 years (range, 2.9-7.5 years).
Six patients died with active disease, including 5 with LCT.
One patient died of treatment-related complications without
active disease. The impact of limited versus advanced stage
disease was significant for PFS (P<.01) and transformation
risk (PZ.02) but not OS (PZ.69). These curves are shown
in Figure 2.
No significant toxicity was attributable to first-line
therapy, although 1 patient did die of salvage treatment
without evidence of disease, as mentioned earlier. Six patients experienced second malignancies, although none
were attributable to treatment. Of the 3 patients in whom
second cancers developed after irradiation, no malignancies
(eg, rectal cancer, pituitary adenoma, and meningioma)
appeared in an irradiated site. For the 3 patients treated with

10

15

Time (years)

Fig. 1.

0.2

0.4

0.6

0.8

Non-Rituxmab (n=7)
Rituximab (n=7)
Observation (n=4)

0.0

Radiation (n=9)
Response-adaptive (n=16)
Rituximab (n=9)
Observation (n=3)

Progression-Free Survival (Probability)

0.4

0.6

0.8

1.0

0.2

Progression-Free Survival (Probability)

1.0

International Journal of Radiation Oncology  Biology  Physics

King et al.

0.0

72

10

15

Time (years)

Kaplan-Meier plots of progression-free survival based on treatment type for (a) limited and (b) advanced stage.

rituximab, malignancies included melanoma, and lobular

carcinoma in situ (nZ2).

Discussion
Our single-institution experience in treating NLPHL is
unique, in that the majority of patients participated on
prospective clinical protocols that de-escalated treatment
for limited disease. Almost all pediatric patients were
enrolled on response-adaptive therapy protocols, which
reduced radiation dose or eliminated RT based on their
interim response to chemotherapy. Many adult patients
were enrolled on a rituximab monotherapy protocol. We
performed an analysis comparing these 2 de-escalated
treatments with standard RT alone for limited disease.
The 5-year PFS for the 9 patients (2 stage I, 7 stage II)
who received RT alone was 100%. This result compared
relatively favorably with the 5-year PFS values of 95% for
stage I and 86% for stage II disease as reported in a large
single-institution series (6). However, it is important to note
the smaller sample size and the shorter median follow-up
time (5.0 years) for RT alone in this study.
Pediatric patients who participated in response-adaptive
therapy protocols achieved a PFS (5-year PFS of 93.8%;
95% CI: 82.6-100) similar to that of the adult patients
treated with RT alone. Two of 3 patients who achieved an
interim PR experienced relapse despite receiving 25.5 Gy
RT. By contrast, none of the 13 patients who achieved an
interim CR after chemotherapy experienced relapse,
whether or not 15 Gy RT was administered. These results
can be compared with those from 2 reported trials for
favorable disease from the Pediatric Hodgkin Lymphoma
Consortium. In the earlier trial, none of the 28 patients, who
achieved an interim CR after VAMP chemotherapy and
received dose de-escalated RT (15 Gy) experienced relapse
(8). However, in the later trial, 4 of 26 patients, who

achieved an interim CR after VAMP chemotherapy and did

not receive RT experienced relapse (9). All 4 patients with
relapse had stage IIA disease, whereas none of the 10 patients with completely resected IA disease experienced
relapse. Taken together, these data suggest that responseadaptive therapy with VAMP chemotherapy and RT dose
de-escalation may be a suitable alternative to RT alone for
patients with favorable disease. However, elimination of RT
after VAMP chemotherapy should be reserved for patients
with completely resected stage IA disease who achieve CR.
Other response-adaptive protocols for children with
NLPHL have been published. In the Childrens Cancer
Group 5942 trial, 52 patients received 4 to 6 cycles of
COPP (cyclophosphamide, vincristine, procarbazine,
prednisone)/ABV chemotherapy without RT; 47 patients
achieved CR, and only 2 patients experienced relapse (25).
Another recent Childrens Oncology Group study, AHOD
03P1, included patients who had incompletely resected IA
or IIA disease. These patients received response-adaptive
therapy with 3 cycles of AV-PC (doxorubicin, vincristine,
prednisone, and cyclophosphamide). Of the 126 patients
who achieved CR and did not receive RT, 13 experienced
relapse (26). Current response-adaptive therapy trials
involving Stanford V chemotherapy for favorable and
intermediate-risk disease are ongoing (23, 24). If promising
results are obtained, future response-adaptive trials with RT
dose reduction in the younger adult population, who are
also at risk for late effects including secondary malignancies, may be considered (27).
In the 9 patients with limited disease who received rituximab monotherapy, PFS was worse than in those who
received RT alone. This result is consistent with a previous
report by our group (11) and with a rituximab monotherapy
trial for stage IA disease by the German Hodgkin Study
Group (GHSG) (10). Taken together, these data suggest that
rituximab alone is inappropriate for patients with limited
disease.

Volume 92  Number 1  2015

Table 4

Lymphocyte predominant Hodgkin lymphoma

73

Clinical outcomes for advanced disease based on treatment modality

Characteristic

Non-rituximab

Rituximab

Observation

Total

No.
Age, y
21
Stage
III
IV
Baseline factors
B symptoms
Extranodal site
3 or more sites
Infradiaphragmatic*
>5 cm lymphadenopathy
ESR
Elevated
Missing
Variant histology
PET/CT staging
Follow-up time, y
Median (range)
Treatment response
Complete response
Partial response
Progression
Biopsy confirmed
Time of progression
5-year PFS (95% CI)
No. at risk
LCT
Time of LCT
Death
Nontransformed NLPHL
Transformed NLPHL
No evidence of NLPHL
Time of death

7
25 (10-52)
3

7
46 (18-85)
1

4
51 (39-73)
0

18
42 (10-85)
4

7
0

4
0

18
0

0
0
6
6 (5)
0

1
0
1
1 (0)
0

2
0
13
12 (5)
4

0
3
1
6

0
1
0
3

1
7
4
13

1.6 (0.9-10.9)

8.6 (2.9-14.2)

10.6 (3.5-14.9)

7.6 (0.9-14.9)

4
3
2
0
4.8 (2.9-6.7)
66.7 (30.0-100.0)
2
0
NA
1
1
0
0
6.8

2
5
6
5
2.0 (0.7-6.2)
28.6 (8.9-92.2)
2
6
4.5 (1.2-8.3)
2
0
2
0
4.2 (2.9, 5.4)

NA
NA
4
0
2.1 (0.5-3.8)
0
0
0
NA
0
0
0
0
NA

6
8
12
5
2.1 (0.5-6.7)
29.9 (13.3-7.4)
4
6
4.5 (1.2-8.3)
3
1
2
0
5.4 (2.9, 6.8)

7
0
1
0
6
5 (0)
4
1
3
3
4

Abbreviations: CI Z confidence interval; CT Z computed tomography; ESR Z elevated sedimentation rate; LCT Z large cell transformation;
NLPHL Z nodular lymphocyte predominant Hodgkin lymphoma; PET Z positron emission tomography; PFS Z progression-free survival.
* Under infradiaphragmatic, number within parentheses represents number of patients in whom transformed disease developed.

Other dose de-escalation strategies have also been published. With regard to surgical resection alone in pediatric
patients, the COG study AHOD 03P1 included 52 additional patients with completely resected stage IA disease;
of those, 12 patients experienced relapse (26). In the
EuroNET-PHL trial, 14 of 51 patients who achieved CR
after surgery experienced relapse (5-year PFS, 67%) (12).
With respect to low-dose involved field RT for adults, a
retrospective series described 9 patients (3 with new diagnoses, 6 with relapse) with 1 or 2 involved sites, who
received 4 Gy in 2 fractions. Five patients experienced
disease progression (16). The clinical outcomes for both of
these de-escalated treatments appear inferior to those of
definitive RT alone and of response-adaptive therapy.
For advanced disease, there was no significant difference
in PFS between rituximab (5-year PFS 28.6% [8.9, 92.2]) and
non-rituximab (5-year PFS 66.7% [30.0, 100.0]) treatments.
However, our analysis was limited by small sample size,

short follow-up time (median, 1.5 years), and heterogeneous

treatment techniques (3 chemotherapy alone, 2 CMT, and 2
response-adaptive) for the non-rituximab cohort. Other
studies have reported better outcomes with chemotherapy. A
previous study by GHSG reported a 4.2-year freedom from
treatment failure (FFTF) rate of 77% (2). A study from the
British Columbia Cancer Agency (BCCA) reported 5 and 15year FFTF rates of 82% and 52% (28). Therefore, rituximab
may be appropriate only for patients with advanced disease
who are not fit for chemotherapy.
In our series, 9 of 55 patients (16%) experienced LCT at
a median follow-up time of 6.5 years. Although 8 of 9
patients with LCT had received rituximab monotherapy,
either at diagnosis (nZ7) or at relapse (nZ1), 5 patients
had both infradiaphragmatic involvement and advanced
disease at diagnosis. Furthermore, 5 of the 7 patients who
died had pathologic evidence of LCT. These clinical findings are consistent with those reported in the literature. A

International Journal of Radiation Oncology  Biology  Physics

1.0
0.8
0.6
0.0

Limited
Advanced

Limited
Advanced

0.4

0.4

0.6

0.8

Transformation Risk (Probability)

1.0

0.2

Progression-Free Survival (Probability)

0.2

King et al.

0.0

74

10

15

Time (years)

0.8
0.6
0.4
0.2

Limited
Advanced

0.0

Overall Survival (Probability)

15

1.0

Time (years)

10

10

15

Time (years)

Fig. 2. Kaplan-Meier plots of (a) progression-free survival, (b) transformation risk, and (c) overall survival for limited
(nZ37) or advanced (nZ18) disease.

French registry-based study noted that patients in whom

LCT developed at the time of relapse showed inferior OS
(29). A report from the BCCA identified splenic involvement and advanced disease as risk factors for the development of LCT (4). Infradiaphragmatic involvement was
also identified a risk factor in the prospective study of rituximab published by our group (11). Our series provides
further evidence that LCT is an important clinical endpoint
that should be monitored with long-term follow-up. This
endpoint may be especially important because the results
with R-CHOP have shown promise for the treatment of
advanced NLPHL (30). In that study, no relapses or transformations were reported over a short median follow-up
time of 3.5 years.
The GHSG recently identified variant histology, as classified by our group (19), as an independent prognostic factor
for relapse, progression, or both (31). We could not evaluate
the association between variant histology and treatment efficacy because of the limited patient numbers. However, an
interesting finding is that 3 patients with variant histology

who received response-adaptive therapy did not experience

relapse after an interim CR followed by 15 Gy RT.
This study has important limitations. First, it was a
single-institution retrospective analysis. Second, it included
a heterogeneous mixture of patients, including both children and adults, treated with multiple different modalities
on differing clinical protocols. Third, the cohorts for
treatment modalities that were not analyzed prospectively
often contained fewer patients with more limited follow-up
times. Fourth, actual pathology tissue blocks were not
available for formal repeated analysis of variant histology
in all patients. Nevertheless, this study provides insight into
many of the evolving investigational trends for the treatment of NLPHL.

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Volume 92  Number 1  2015

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