Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma in the Modern Era

Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma in the Modern Era

International Journal of Radiation Oncology biology physics www.redjournal.org Clinical Investigation Management of Nodular Lymphocyte Predominan...

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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: [email protected] 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 Ó 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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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. Ó 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 CD30þ and CD15þ Hodgkin/Reed-Sternberg cells, the large atypical cells of NLPHL are uniformly CD20þ (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 CD20þ, 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,

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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, 3þ sites Favorable

9/1990-2/2000

Regimen

Radiation therapy

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

VAMP

4

CT

25.5

15

VAMP

4

PET/CT

25.5

0

VAMP/COP

6

CT

25.5

15

PET/CT

25.5

0

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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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%,

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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

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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

0

5

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

b

0.2

Progression-Free Survival (Probability)

a

1.0

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0

5

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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 Children’s 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 Children’s 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.

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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

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1.0 0.8 0.6 0.0

Limited Advanced

Limited Advanced

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Limited Advanced

0.0

Overall Survival (Probability)

c

15

1.0

Time (years)

10

0

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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.

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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