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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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. 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,
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
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.
68
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. 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,
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
