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International Journal of
Radiation Oncologybiology physics
www.redjournal.org
Clinical Investigation
Management of Nodular LymphocytePredominant Hodgkin Lymphoma in theModern EraMartin 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 CancerInstitute, Stanford, California
Received Oct 21, 2014, and in revised form Jan 15, 2015. Accepted for publication Feb 2, 2015.
Summary
A single-institution analysisof nodular lymphocyte pre-dominant Hodgkin lym-phoma between 1996 and2013 was conducted. Forlimited-stage (I-II) disease,response-adaptive therapy, inwhich radiation therapy (RT)dose was reduced or elimi-nated after initial chemo-therapy, demonstratedoutcomes comparable withthose of RT alone. Rituximabmonotherapy demonstratedinferior outcomes for limiteddisease and a high relapserate for advanced-stage (III-IV) disease.
Reprint requests to: Martin King, MD, PhD
Stanford, CA 94305. Tel: (650)725-4782; E-ma
Presented in part at the 56th Annual Meetin
for Radiation Oncology in San Francisco, C
17, 2014.
Int J Radiation Oncol Biol Phys, Vol. 92, No. 1
0360-3016/$ - see front matter � 2015 Elsevie
http://dx.doi.org/10.1016/j.ijrobp.2015.02.001
Purpose: To analyze treatment outcomes for nodular lymphocyte predominant Hodg-kin lymphoma (NLPHL) at a single institution.Patients and Methods: Patients with newly diagnosed NLPHL between 1996 and2013 were reviewed retrospectively. Patients treated before 1996 were excludedbecause the majority received extended field radiation therapy (RT) alone.Results: Fifty-five patients (22 � 21 years old) were identified. The median follow-uptime was 6.8 years. Among 37 patients with limited-stage (I-II) disease, treatmentsincluded involved field RT at a median dose of 36 Gy (nZ9), rituximab monotherapy(nZ9), observation (nZ3), and response-adaptive therapy (nZ16), in which the RTdose was reduced from 25.5 Gy to 15 Gy or was eliminated based on interim imagingafter chemotherapy. The 5-year progression-free survival (PFS) was 76.4% (95% con-fidence interval [CI], 63.1-92.4). Nine patients experienced progression, including 5receiving rituximab, 2 undergoing observation, and 2 receiving response-adaptive ther-apy. 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 sta-tistically significant (PZ.39). Among 18 patients with advanced-stage (III-IV) dis-ease, 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 pro-gression, including 1 receiving chemotherapy, 1 receiving CMT, 6 receiving rituxi-mab, and 4 undergoing observation. There was no significant PFS differencebetween rituximab and non-rituximab therapies (PZ.19) within the caveat of smallsample sizes. In the entire cohort, 9 patients (3 with limited disease, 6 with advanced
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Conflict of interest: none.
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King et al. International Journal of Radiation Oncology � Biology � Physics68
disease) experienced large cell transformation (LCT). Seven patients died; of those, 5died with LCT.Conclusions: For limited disease, response-adaptive therapy demonstrated compara-ble outcomes with RT alone. Rituximab monotherapy resulted in inferior outcomesfor limited disease and a high relapse rate for advanced disease. � 2015 ElsevierInc. All rights reserved.
Introduction
Nodular lymphocyte predominant Hodgkin lymphoma(NLPHL) is an uncommon subtype of lymphoma, withcharacteristics that differentiate it from classical Hodgkinlymphoma (CHL). Whereas CHL is defined by the presenceof CD30þ and CD15þ Hodgkin/Reed-Sternberg cells, thelarge atypical cells of NLPHL are uniformly CD20þ (1).Compared with CHL, NLPHL has a more indolent clinicalcourse and carries a more favorable prognosis (2). How-ever, 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 thesole modality for treating limited-stage (I-II) NHLPL,patient deaths were more often related to treatment (eg,secondary cancers and cardiovascular disease) rather thanto disease progression (5, 6). Recent investigations havefocused on the reduction of late treatment toxicities throughRT field reduction (6, 7) and dose de-escalation. In thepediatric population, response-adaptive therapy, in whichRT dose is reduced (8) or eliminated (9) based on interimimaging response after chemotherapy, has producedpromising results. In the adult population, rituximab (anti-CD20) monoclonal antibody therapy has been evaluated forpatients with newly diagnosed NLPHL, including thosewith limited disease (10, 11). Other strategies that havebeen reported include surgery alone (12), chemotherapyalone (13, 14), combined modality therapy (CMT) (15), andlow-dose involved field RT (16). At our institution, we haveused standard RT alone, we have evaluated response-adaptive therapy for pediatric patients, and we have con-ducted studies to assess rituximab monotherapy.
The goals of this single-institution retrospective studywere 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 rit-uximab monotherapy for limited disease.
Patients and Methods
Patient demographics
We conducted an institutional review boarddapprovedretrospective review of all patients with newly diagnosedNLPHL who were treated at our institution from 1996 to2013. 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 fieldtechniques (17). Patients who presented with relapsedNLPHL and those who had LCT at first presentation werealso excluded. The diagnoses of all patients were recon-firmed by a single expert hematopathologist based onmorphology and immunohistochemical profile (typicallyCD20þ, CD15�, CD30�) as defined by the World HealthOrganization 2008 classification (18).
For each patient, we collected relevant demographic,staging, treatment, and follow-up information. Potentialadverse factors that were specifically evaluated includedpresence of B symptoms, extranodal disease, �3 involvedsites, infradiaphragmatic disease, lymphadenopathymeasuring >5 cm, elevated sedimentation rate, and varianthistology (19, 20). Gross total resection was assigned topatients with stage IA disease who had no clinical orradiographic evidence of residual tumor after excisionalbiopsy. Treatment response was designated as completeresponse (CR) or partial response (PR) based on protocolspecifications if patients were analyzed prospectively. Forpatients who were not treated on protocols, response wasassessed based on reports from era-dependent imagingmodalities (ie, computed tomography [CT] and positronemission tomography [PET]) and the clinical judgmentfrom the treating physician as documented in progressnotes. Radiographic images were not re-reviewed.
Treatment modalities
Treatment modalities included RT alone, chemotherapyalone, CMT, initial observation, response-adaptive therapy,and rituximab monotherapy. For CMT, patients were pre-scribed a course of chemotherapy followed by RT at thetime of consultation. For initial observation, patients hadnot begun treatment within 6 months from initialconsultation.
Pediatric patients receiving response-adaptive therapywere enrolled on, or treated according to, 5 prospectiveprotocols from the Pediatric Hodgkin Lymphoma Con-sortium. As shown in Table 1, protocols were defined forpatients with favorable, intermediate, or unfavorable riskdisease. All protocols consisted of 3 components. Theinitial component was chemotherapy. Regimens included:(1) vinblastine, doxorubicin, methotrexate, and prednisone(VAMP) for 4 total cycles (8, 9); (2) VAMP plus cyclo-phosphamide, vincristine, and procarbazine (COP) for 6total cycles (21); and (3) doxorubicin, vinblastine,
Table 1 Descriptions of response-adaptive protocols defined for patients with favorable, intermediate, and unfavorable risk disease
Protocol RiskEnrollmentperiod Eligibility criteria
Chemotherapy
Interimimaging
Radiation therapy
RegimenNo. ofcycles PR (Gy) CR (Gy)
Donaldson et al (8) Favorable 9/1990-2/2000 I-II, MMR <1/3,no E, <6 cm
VAMP 4 CT 25.5 15
Metzger et al (9) Favorable 3/2000-2/2009 I-II, MMR <1/3,no E, <3 sites
VAMP 4 PET/CT 25.5 0
Hudson et al (21) Unfavorable 10/1993-2/2000 III/IV; I/II with bulky LAN(MMR >1/3 or >6 cm)or B sx
VAMP/COP 6 CT 25.5 15
HOD08 (23) Favorable 2/2009-Enrolling IA/IIA, MMR <1/3, no E,<3 sites
Stanford V 8 wks PET/CT 25.5 0
HOD05 (24) Intermediate 7/2006-Closed IB, IIIA, or IA/IIA withbulky med LAN,E, 3þ sites
Stanford V 12 wks PET/CT 25.5 15
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.
Volume 92 � Number 1 � 2015 Lymphocyte predominant Hodgkin lymphoma 69
mechlorethamine, vincristine, bleomycin, etoposide, andprednisone (Stanford V) (22) for 8 (23) or 12 (24) weeks.The second component was response assessment withinterim imaging (CT or PET/CT), which occurred after 2cycles for VAMP and after 8 weeks for Stanford V. Thethird component was RT. Patients who achieved a PRreceived 25.5 Gy. Those who achieved CR received either15 Gy or no RT based on the protocol open at the time ofdiagnosis. Final results have been reported for the 3 pro-tocols involving VAMP chemotherapy (8, 9, 21). Twopatients, who have completed treatment, are undergoingsurveillance as part of a currently recruiting clinical trial ofreduced duration (8 weeks) Stanford V for favorable dis-ease (23).
For rituximab monotherapy, patients were enrolled on aphase II clinical trial of 4weekly doses of rituximab (375mg/m2).After protocol amendment, patientswere administered 3additional 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 timefrom treatment initiation to relapse, progressive disease, ordate of last follow-up visit if none of these events occurred.For patients designated as undergoing observation, PFS wasassessed from the time of initial consultation to the end-points listed earlier. Transformation risk was assessed fromthe time of initial diagnosis to the time of LCT. Overallsurvival (OS) was assessed from the time of diagnosis tothe last date of follow-up visit or death of any cause. PFS,transformation risk, and OS survival curves were estimatedby Kaplan-Meier analysis. Survival curve comparisonswere performed with the log-rank test. Analysis was
performed with R statistical software version 3.0 (TheR 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, 0.9-15.6 years). The percentage of patients with follow-uptimes longer than 2 and 5 years were 93% and 67%,respectively.
Outcomes for limited disease
Thirty-seven patients presented with limited disease. Thenumber of patients who received RT, response-adaptivetherapy, 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 mediandose of 36 Gy (range, 10-44.6 Gy). All patients achieved aCR. No patient experienced relapse during a medianfollow-up time of 5.0 years.
Sixteen patients underwent response-adaptive therapy.As shown in Table 3, 13 patients had an interim CR tochemotherapy. Six patients (including 3 with variant his-tology) received 15 Gy RT, and 7 were treated withchemotherapy alone. Five patients who received chemo-therapy alone had stage IA disease, and 4 of these 5 un-derwent a gross total resection with no clinical orradiographic evidence of disease after lymph node excision.No patient with an initial CR experienced relapse. Threepatients achieved an interim PR after chemotherapy andreceived 25.5 Gy of RT. All 3 patients had a CR after RT,
Table 2 Clinical outcomes for limited disease based on treatment modality
Characteristic Radiation Response-adaptive Rituximab Observation Total
No. 9 16 9 3 37Age, y 35 (21-51) 9 (5-16) 37 (17-62) 45 (14-58) 21 (5-62)�21 1 16 1 1 19
StageI 2 6 4 1 13II 7 10 5 2 24
Baseline factorsB symptoms 1 0 2 0 3Extranodal site 0 0 0 0 03 or more sites 1 3 2 1 7Infradiaphragmatic* 0 0 1 (0) 1 (1) 2 (1)>5 cm lymphadenopathy 0 1 0 1 2ESRElevated 0 0 2 1 3Missing 2 0 3 1 6
Variant histology 0 3 0 1 4Gross total resection 1 4 1 1 7
Staging PET/CT 7 11 6 2 26Follow-up time, yMedian (range) 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)
Treatment responseComplete response 9 16 6 NA 31Partial response 0 0 3 NA 3
Progression 0 2 5 2 9Biopsy confirmed 0 2 1 1 4Time of progression NA 4.2 (1.9-6.5) 2.6 (1.6-4.6) 1.8 (0.4-3.1) 2.6 (0.4-6.5)
5-year PFS (95% CI) 100 93.8 (82.6-100) 40.0 (17.1-3.8) NA 76.4 (63.1-2.4)No. at risk 5 13 2 0 20
LCT 0 1 1 1 3Time of LCT NA 6.6 3.2 6.5 6.5 (3.2-6.6)
Death 0 2 1 1 4Nontransformed NLPHL 0 0 0 0 0Transformed NLPHL 0 1 1 1 3No evidence of NLPHL 0 1 0 0 1
Time of death NA 7.4 (7.4, 7.5) 7.5 6.6 7.4 (6.6-7.5)
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.
King et al. International Journal of Radiation Oncology � Biology � Physics70
but 2 patients subsequently experienced relapse. One pa-tient with favorable disease (stage IIA disease, mediastinalmass ratio <1/3, no extranodal site, <6 cm tumor) expe-rienced relapse with LCT outside of the previously irradi-ated field at 6.6 years, and died of disease progression at7.5 years. Another patient with unfavorable disease (stageIIA disease, >6 cm nodal mass) who received 25.5 Gy RTexperienced relapse within the irradiated field at 1.9 years.He underwent multiple salvage treatments, including re-irradiation and 2 stem-cell transplantations, and died ofdisseminated histoplasmosis with no evidence of lym-phoma at 7.4 years.
Of the 9 patients treated with rituximab, 4 receivedadditional maintenance therapy. Six patients achieved aCR. Five patients experienced progression at a median timeof 2.6 years. One patient with limited stage IA diseaseexperienced LCT at 3.2 years. He received salvage therapy
with rituximab, cyclophosphamide, doxorubicin, vincris-tine, and prednisone (R-CHOP) followed by RT but died ofan unknown cause with active disease at 7.5 years.
For initial observation, 1 patient with infradiaphragmaticdisease and variant histology at diagnosis experiencedprogression after 0.4 years and was treated subsequentlywith rituximab monotherapy. She then experienced rapidlyprogressive disease refractory to multiple chemotherapyregimens and died of LCT at 6.6 years. Another patientexperienced progression at 3.1 years and underwentsalvage therapy with CMT. A third patient with stage IIAdisease had not experienced progression after 4.6 years offollow-up.
For the entire limited-stage cohort, 9 of 37 patientsexperienced relapse or progression. Three experiencedLCT. The 5-year PFS, transformation risk, and OS were76.4% (95% CI: 63.1, 92.4), 3.2% (0, 9.2) and 100%,
Table 3 Patients receiving response-adaptive therapy withlimited disease stratified by interim imaging response (CR orPR) and treatment (chemo or CMT)
Characteristic CR-ChemoCR-CMT15 Gy
PR-CMT25 Gy
No. 7 6 3Stage
IA 5 1 0IIA 2 5 3
RiskFavorable 7 5 2Intermediate 0 1 0Unfavorable 0 0 1
ChemotherapyVAMP � 4 cycles 6 5 1VAMP/COP � 6cycles
0 0 1
Stanford V � 8weeks
1 0 1
StanfordV � 12 weeks
0 1 0
Gross tumor resection 4 0 0Follow-up time, y
Median (range) 7.5(3.1-12.8)
8.4(5.1-12.5)
7.4(3.9-7.5)
OutcomesRelapse 0 0 2Transform 0 0 1Death 0 0 2
Abbreviations: Chemo Z chemotherapy; CMT Z combined mo-
dality 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.
Volume 92 � Number 1 � 2015 Lymphocyte predominant Hodgkin lymphoma 71
respectively. The estimated 5-year PFS values by treatmentmodality were 100% for RT alone, 93.8% (82.6, 100) forresponse-adaptive therapy, and 40.0% (17.1, 93.8) for rit-uximab. Rituximab was associated with an inferior PFScompared with RT alone (PZ.02), as shown in Figure 1a.By contrast, there was no significant difference in PFSbetween response-adaptive therapy and RT alone (PZ.39).There was also no significant difference in PFS betweenpediatric 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. Patientswho were treated with chemotherapy alone (nZ3), CMT(nZ2), and response-adaptive therapy (nZ2), wereaggregated into a “non-rituximab” category, as shown inTable 4. The 3 patients treated with chemotherapy alonereceived 6 cycles of doxorubicin, bleomycin, vinblastine,and dacarbazine (ABVD). One patient experienced
progression at 2.9 years. Two patients receiving CMTreceived chemotherapy (Stanford V for 12 weeks and R-CHOP for 6 cycles) followed by 30.6 Gy RT to >5 cmnodal conglomerates. The patient who received Stanford Valso had variant histology at diagnosis and died withrelapsed disease at 6.8 years. Of 2 patients who receivedresponse-adaptive therapy, 1 patient received 15 Gy for aninterim CR, and the other received 25.5 Gy for an interimPR. Neither patient experienced relapse. Of note, the me-dian follow-up time of 1.6 years for the non-rituximabcohort was limited.
All 4 patients undergoing observation experienced pro-gression at 4 years. Two patients were treated with ritux-imab monotherapy, and the third received an unspecifiedrituximab-chemotherapy combination. One patient hadnever received salvage therapy at 10.7 years follow-up.
Among the 7 patients who received rituximab mono-therapy, 1 received additional maintenance therapy. Sixpatients experienced progression at a median time of2.0 years. All 6 experienced LCT at a median time of4.5 years. Of note, 5 patients had infradiaphragmatic dis-ease at presentation, 1 patient had variant histology, and 4patients presented with LCT at first relapse. Two patientsdied of LCT at 2.9 and 5.4 years.
For advanced disease, 12 of 18 patients experiencedrelapse or progression. Six of the 7 patients who receivedrituximab experienced LCT. The 5-year PFS, trans-formation risk, and OS rates were 29.9% (13.3, 67.4),21.0% (0, 39.6), and 92.9% (80.3, 100), respectively. Theestimated 5-year PFS values were 66.7% (30, 100) for non-rituximab treatments, 28.6% (8.9, 92.2) for rituximab, and0% for observation. The difference in PFS between ritux-imab and non-rituximab treatments (excluding observation)was not significant (PZ.19).
Outcomes for entire cohort
Among all 55 patients, 21 patients experienced relapse orprogression at a median time of 2.1 years (range, 0.4-6.7 years). Nine patients (16%) experienced LCT at a me-dian time of 6.5 years (range, 1.2-8.3 years). Seven patientsdied 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 withoutactive disease. The impact of limited versus advanced stagedisease was significant for PFS (P<.01) and transformationrisk (PZ.02) but not OS (PZ.69). These curves are shownin Figure 2.
No significant toxicity was attributable to first-linetherapy, although 1 patient did die of salvage treatmentwithout evidence of disease, as mentioned earlier. Six pa-tients experienced second malignancies, although nonewere attributable to treatment. Of the 3 patients in whomsecond cancers developed after irradiation, no malignancies(eg, rectal cancer, pituitary adenoma, and meningioma)appeared in an irradiated site. For the 3 patients treated with
0 5 10 15 0 5 10 15
Time (years) Time (years)
Radiation (n=9)Response-adaptive (n=16)Rituximab (n=9)Observation (n=3)
Non-Rituxmab (n=7)Rituximab (n=7)Observation (n=4)
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Fig. 1. Kaplan-Meier plots of progression-free survival based on treatment type for (a) limited and (b) advanced stage.
King et al. International Journal of Radiation Oncology � Biology � Physics72
rituximab, malignancies included melanoma, and lobularcarcinoma in situ (nZ2).
Discussion
Our single-institution experience in treating NLPHL isunique, in that the majority of patients participated onprospective clinical protocols that de-escalated treatmentfor limited disease. Almost all pediatric patients wereenrolled on response-adaptive therapy protocols, whichreduced radiation dose or eliminated RT based on theirinterim response to chemotherapy. Many adult patientswere enrolled on a rituximab monotherapy protocol. Weperformed an analysis comparing these 2 de-escalatedtreatments 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 comparedrelatively favorably with the 5-year PFS values of 95% forstage I and 86% for stage II disease as reported in a largesingle-institution series (6). However, it is important to notethe smaller sample size and the shorter median follow-uptime (5.0 years) for RT alone in this study.
Pediatric patients who participated in response-adaptivetherapy protocols achieved a PFS (5-year PFS of 93.8%;95% CI: 82.6-100) similar to that of the adult patientstreated with RT alone. Two of 3 patients who achieved aninterim PR experienced relapse despite receiving 25.5 GyRT. By contrast, none of the 13 patients who achieved aninterim CR after chemotherapy experienced relapse,whether or not 15 Gy RT was administered. These resultscan be compared with those from 2 reported trials forfavorable disease from the Pediatric Hodgkin LymphomaConsortium. In the earlier trial, none of the 28 patients, whoachieved an interim CR after VAMP chemotherapy andreceived 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 didnot receive RT experienced relapse (9). All 4 patients withrelapse had stage IIA disease, whereas none of the 10 pa-tients with completely resected IA disease experiencedrelapse. Taken together, these data suggest that response-adaptive therapy with VAMP chemotherapy and RT dosede-escalation may be a suitable alternative to RT alone forpatients with favorable disease. However, elimination of RTafter VAMP chemotherapy should be reserved for patientswith completely resected stage IA disease who achieve CR.
Other response-adaptive protocols for children withNLPHL have been published. In the Children’s CancerGroup 5942 trial, 52 patients received 4 to 6 cycles ofCOPP (cyclophosphamide, vincristine, procarbazine,prednisone)/ABV chemotherapy without RT; 47 patientsachieved CR, and only 2 patients experienced relapse (25).Another recent Children’s Oncology Group study, AHOD03P1, included patients who had incompletely resected IAor IIA disease. These patients received response-adaptivetherapy with 3 cycles of AV-PC (doxorubicin, vincristine,prednisone, and cyclophosphamide). Of the 126 patientswho achieved CR and did not receive RT, 13 experiencedrelapse (26). Current response-adaptive therapy trialsinvolving Stanford V chemotherapy for favorable andintermediate-risk disease are ongoing (23, 24). If promisingresults are obtained, future response-adaptive trials with RTdose reduction in the younger adult population, who arealso at risk for late effects including secondary malig-nancies, may be considered (27).
In the 9 patients with limited disease who received rit-uximab monotherapy, PFS was worse than in those whoreceived RT alone. This result is consistent with a previousreport by our group (11) and with a rituximab monotherapytrial for stage IA disease by the German Hodgkin StudyGroup (GHSG) (10). Taken together, these data suggest thatrituximab alone is inappropriate for patients with limiteddisease.
Table 4 Clinical outcomes for advanced disease based on treatment modality
Characteristic Non-rituximab Rituximab Observation Total
No. 7 7 4 18Age, y 25 (10-52) 46 (18-85) 51 (39-73) 42 (10-85)
�21 3 1 0 4Stage
III 7 7 4 18IV 0 0 0 0
Baseline factorsB symptoms 1 0 1 2Extranodal site 0 0 0 03 or more sites 6 6 1 13Infradiaphragmatic* 5 (0) 6 (5) 1 (0) 12 (5)>5 cm lymphadenopathy 4 0 0 4ESRElevated 1 0 0 1Missing 3 3 1 7
Variant histology 3 1 0 4PET/CT staging 4 6 3 13Follow-up time, y
Median (range) 1.6 (0.9-10.9) 8.6 (2.9-14.2) 10.6 (3.5-14.9) 7.6 (0.9-14.9)Treatment response
Complete response 4 2 NA 6Partial response 3 5 NA 8
Progression 2 6 4 12Biopsy confirmed 0 5 0 5Time of progression 4.8 (2.9-6.7) 2.0 (0.7-6.2) 2.1 (0.5-3.8) 2.1 (0.5-6.7)
5-year PFS (95% CI) 66.7 (30.0-100.0) 28.6 (8.9-92.2) 0 29.9 (13.3-7.4)No. at risk 2 2 0 4
LCT 0 6 0 6Time of LCT NA 4.5 (1.2-8.3) NA 4.5 (1.2-8.3)
Death 1 2 0 3Nontransformed NLPHL 1 0 0 1Transformed NLPHL 0 2 0 2No evidence of NLPHL 0 0 0 0
Time of death 6.8 4.2 (2.9, 5.4) NA 5.4 (2.9, 6.8)
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.
Volume 92 � Number 1 � 2015 Lymphocyte predominant Hodgkin lymphoma 73
Other dose de-escalation strategies have also been pub-lished. With regard to surgical resection alone in pediatricpatients, the COG study AHOD 03P1 included 52 addi-tional patients with completely resected stage IA disease;of those, 12 patients experienced relapse (26). In theEuroNET-PHL trial, 14 of 51 patients who achieved CRafter surgery experienced relapse (5-year PFS, 67%) (12).With respect to low-dose involved field RT for adults, aretrospective series described 9 patients (3 with new di-agnoses, 6 with relapse) with 1 or 2 involved sites, whoreceived 4 Gy in 2 fractions. Five patients experienceddisease progression (16). The clinical outcomes for both ofthese de-escalated treatments appear inferior to those ofdefinitive RT alone and of response-adaptive therapy.
For advanced disease, there was no significant differencein PFS between rituximab (5-year PFS 28.6% [8.9, 92.2]) andnon-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 heterogeneoustreatment techniques (3 chemotherapy alone, 2 CMT, and 2response-adaptive) for the non-rituximab cohort. Otherstudies have reported better outcomes with chemotherapy. Aprevious study by GHSG reported a 4.2-year freedom fromtreatment failure (FFTF) rate of 77% (2). A study from theBritish ColumbiaCancer Agency (BCCA) reported 5 and 15-year FFTF rates of 82% and 52% (28). Therefore, rituximabmay be appropriate only for patients with advanced diseasewho are not fit for chemotherapy.
In our series, 9 of 55 patients (16%) experienced LCT ata median follow-up time of 6.5 years. Although 8 of 9patients with LCT had received rituximab monotherapy,either at diagnosis (nZ7) or at relapse (nZ1), 5 patientshad both infradiaphragmatic involvement and advanceddisease at diagnosis. Furthermore, 5 of the 7 patients whodied had pathologic evidence of LCT. These clinical find-ings are consistent with those reported in the literature. A
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Fig. 2. Kaplan-Meier plots of (a) progression-free survival, (b) transformation risk, and (c) overall survival for limited(nZ37) or advanced (nZ18) disease.
King et al. International Journal of Radiation Oncology � Biology � Physics74
French registry-based study noted that patients in whomLCT developed at the time of relapse showed inferior OS(29). A report from the BCCA identified splenic involve-ment and advanced disease as risk factors for the devel-opment of LCT (4). Infradiaphragmatic involvement wasalso identified a risk factor in the prospective study of rit-uximab published by our group (11). Our series providesfurther evidence that LCT is an important clinical endpointthat should be monitored with long-term follow-up. Thisendpoint may be especially important because the resultswith R-CHOP have shown promise for the treatment ofadvanced NLPHL (30). In that study, no relapses or trans-formations were reported over a short median follow-uptime of 3.5 years.
The GHSG recently identified variant histology, as clas-sified by our group (19), as an independent prognostic factorfor relapse, progression, or both (31). We could not evaluatethe association between variant histology and treatment ef-ficacy because of the limited patient numbers. However, aninteresting finding is that 3 patients with variant histology
who received response-adaptive therapy did not experiencerelapse after an interim CR followed by 15 Gy RT.
This study has important limitations. First, it was asingle-institution retrospective analysis. Second, it includeda heterogeneous mixture of patients, including both chil-dren and adults, treated with multiple different modalitieson differing clinical protocols. Third, the cohorts fortreatment modalities that were not analyzed prospectivelyoften contained fewer patients with more limited follow-uptimes. Fourth, actual pathology tissue blocks were notavailable for formal repeated analysis of variant histologyin all patients. Nevertheless, this study provides insight intomany of the evolving investigational trends for the treat-ment of NLPHL.
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