Abstract
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct subtype of Hodgkin lymphoma characterized by unique clinical presentation, histological appearance, and indolent disease course. The recurrent nature of disease provides an opportunity to examine the role of stem cell transplant in its management. We report here a single center experience of 26 patients with relapsed NLPHL treated with high-dose chemotherapy and autologous stem cell transplantation between 1990 and 2008. With a median follow up of 50 months (range, 2-138 months), the 5-year overall (OS) and event-free survival (EFS) were 76% (SE 9%) and 69% (SE 10%), respectively. Our data suggests that the high-dose chemotherapy and autologous transplantation should be considered as an option for patients with relapsed NLPHL.
Introduction
Of the 8,000 cases of Hodgkin lymphoma (HL) diagnosed in the US each year, 5-10% are further classified as nodular lymphocyte predominant HL (NLPHL). Descriptions of NLPHL first appeared in the literature in 1936, with the extent of lymphocyte proliferation in the involved lymph nodes suggestive of an improvement in overall survival. 1 In 1994, the revised European American classification of lymphoid neoplasms recognized this rare clinico-pathological entity of NLPHL not only on the basis of lymphocyte predominance, but also the presence of larger atypical, CD20 positive cells known as lymphocyte-predominant (LP) cells, previously called L & H cells or Reed-Sternberg cell variants.2 The publication of nearly two dozen retrospective series has elucidated clinical features of greater than 1500 cases of HL. Clinical features distinguishing NLPHL from Classical HL include a greater male predominance (3:1), older median age at presentation (30-40 years), and lower incidence of mediastinal involvement (<15%). Additionally, certain risk factors classically associated with HL (including presence of B-symptoms, elevated ESR, bulky disease, and multiple sites of nodal involvement) are less prevalent. 1
The majority of patients present with limited stage disease and response rates to primary therapy exceeding 90%. However, 10-35% of patients relapse after achieving an initial complete remission, with a median time to first relapse of 3-6 years.1 Data has shown that those with early unfavorable and advanced stages of NLPHL have outcomes similar to those with classical HL. Although not evidence based, the treatment of advanced stage NLPHL typically includes rituximab in combination with either ABVD or CHOP, given that the malignant cells of NLPHL express the CD20 antigen.11-13 Such therapy is associated with long term remissions in many, but eventually some patients will relapse. At present, there is no uniform data on the outcome of second-line therapy, as there is no consensus on which type of treatment should be utilized. Furthermore, the role of autologous stem cell transplant (ASCT) in this setting remains poorly described. In this study, we report our experience with ASCT for relapsed NLPHL.
Methods
The selected study population included 26 patients with relapsed NLPHL who underwent high- dose chemotherapy and autologous transplantation at The University of Texas MD Anderson Cancer Center between January 1990 and December 2008. Data were collected from an institutional database of blood and marrow transplant recipients and from review of patient records. The institutional review board approved this retrospective review. All pathology specimens were reviewed by pathologists at M. D. Anderson to ensure concordance with the WHO 2008 criteria. According to the WHO 2008 guidelines, NLPHL is characterized by the presence of a nodular proliferation of scattered neoplastic cells, known as LP cells, occurring in a background of non-neoplastic lymphocytes and histiocytes infiltrating a network of follicular dendritic cells. Of the 26 patients, 8 (31%) were noted to have transformation of their disease to large cell lymphoma (LCL) at the time of relapse.5
Responsiveness to therapy was assessed using the “International Workshop Criteria” published in 1999.6 Patients were recognized either as having a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). They were also classified on the basis of chemosensitivity, with those with either PR or CR prior to transplantation defined as being “chemosensitive”.
Probabilities of outcomes were calculated utilizing the Kaplan-Meir method. Both overall survival (OS) and event-free survival (EFS) were measured in months, starting from the date of transplantation. EFS indicated the time to disease relapse, progression, or death independent of cause.
Results and Discussion
Patient characteristics are summarized in Table 1. At the time of transplantation, 9 patients (35%) were in CR; 13 patients (50%) were in PR; and 4 patients (15%) had SD or PD. At the time of transplant 18 patients (70%) had histology consistent with NLPHL, and 8 (30%) with evidence of transformation to LCL. Seven of 18 patients (39%) who were histologically proven to have NLPHL at the time of relapse had advanced disease at the time of initial diagnosis, as compared to 6 of 8 (75%) with ultimate transformation to large cell lymphoma. At the time of relapse, a vast majority of patients with both NLPHL and transformed large cell lymphoma had advanced stage disease; 17 of 18 patients (94%) with NLPHL and 8 of 8 (100%) with transformed disease. Although LDH was not available in all patients at relapse, it was elevated in 3 of 10 (30%) of patients with NLPHL and 2 of 7 (29%) with transformed large cell lymphoma. Seven patients (27%) had the presence of B symptoms at the time of transplantation. Pre-transplant lactate dehydrogenase was elevated in 10 of 22 patients (38%). Median age at time of transplantation was 35 years (range 13-51).
Table I. Patient Characteristics: (n=26).
| Characteristic | Number |
|---|---|
| Age | |
| Median (range) years | 35 (13-51) |
| Sex | |
| Male | 24 (92.3) |
| Female | 2 (7.7) |
| Stage at Diagnosis | |
| I | 5 (19.2) |
| II | 6 (23) |
| III | 9 (34.6) |
| IV | 5 (19.2) |
| Unknown | 1 (3.8) |
| B Symptoms | 7 (26.9) |
| Number of prior chemotherapy regimens | |
| Median (range) | 3 (1-4) |
| Prior radiation therapy | 12 (46.2) |
| Prior Rituximab | 14 (53.8) |
| Disease status at transplant | |
| Complete remission | 9 (34.6) |
| Partial remission | 13 (50) |
| Stable disease | 1 (3.8) |
| Progressive disease | 3 (11.5) |
|
Median duration from time of diagnosis to time
of auto transplant |
35.2 mos (9.2-439.4) |
| Chemosensitivity | |
| Chemosensitive | 22 (84.6) |
| Chemo resistant | 4 (15.3) |
| Stem cell source | |
| Bone Marrow | 3 (11.5) |
| Peripheral Blood | 23 (88.4) |
| Lactate Dehydrogenase at transplant | |
| Abnormal | 10 (38.5) |
| Conditioning Regimen | |
| BEAM –R | 10 (38.5) |
| BEAM | 5 (19.2) |
| CBV | 6 (23) |
| Other* | 5 (19.2) |
| Histology at transplantation | |
| NLPHL | 18 (69.2) |
| Large cell lymphoma | 8 (30.7) |
Abbreviations: BEAM,(carmustine, etoposide, cytarabine, and melphalan); CBV (cyclophosphamide, carmustine, and etoposide); BEAM-R (carmustine, etoposide, cytarabine, melphalan, and rituximab).
included: Busulfan/Melphalen, Mitoxantrone/Etoposide/Thiotepa, BEAM-R/Zevalin, BEAC (carmustine, etoposide, cytarabine, melphalan, and cyclophosphamide)
Median number of prior chemotherapy regimens was 3 (range 1-4), and 12 patients (46.2%) were treated with IFRT prior to transplant. Fourteen patients (53.8%) received rituximab; 4 in the first line setting, 11 in the salvage setting, and 9 as a part of their conditioning regimen prior to transplant.
The median duration of time from initial diagnosis to autologous transplant was 35.2 months (range 9.2-439.4 months). Conditioning regimens utilized in order of frequency, from highest to lowest, were R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan), CBV (cyclophosphamide, carmustine, and etoposide), and BEAM (carmustine, etoposide, cytarabine, and melphalan). The remaining 5 patients were treated with various other conditioning regimens. Peripheral blood stem cells were used as stem cell source in 23 (86%) patients. All patients engrafted following transplantation.
Following transplantation, 22 patients were in complete remission. No treatment related mortality or treatment related myelodysplastic syndrome/acute myelogenous leukemia occurred in any of the patients included in the study. Ultimately, seven patients relapsed. Among them, only one relapsed with diffuse large B-cell lymphoma DLBCL whilst the remainder had return of their NLPHL. Three out of 4 patients (75%) with chemoresistent disease relapsed as compared to 4 out of 22 (18%) patients with chemosensitive disease.
As summarized in Table 2, the 5-year OS and EFS at a median follow-up period of 50 months (range 2-138 months) were 76% (SE 9%) and 69% (SE 10%), respectively. In patients with chemosensitive disease, the 5-year overall-survival (OS) and event-free survival (EFS) were 82% (SE 10%) and 79% (SE 10%), respectively. Of the 26 patients in the series, 18 patients had relapse of their original histology of NLPHL at the time of transplant, and 8 patients transformed to Large-cell lymphoma (LCL). The 5 year EFS) and OS for those with NLPHL were 61% (SE 12%) and 73% (12%) respectively. For those with transformation to LCL at the time of transplant, EFS and OS were 87% (12%) and 87% (12%) respectively. At the conclusion of the follow-up period, 6 deaths occurred on account of progressive disease.
Table II. Patient Outcome (N=26).
| Engraftment | |
|---|---|
| Absolute neutrophil count>500/mm3 | 10 (8-33) days |
| Platelets >20,000/mm3 | 10 (7-35) days |
| Median Follow-up | 50 (2-138) months |
| Cause of Death | |
| Disease progression | 6 |
| Non-relapse mortality | 0 |
| Event-free survival at 5 years | 69% (SE 10%) |
| Overall survival at 5 years | 76% (SE 10%) |
| Chemosensitive patients | |
| Event-free survival at 5 years | 79% (SE 10) |
| Overall survival at 5 years | 82% (SE 10) |
| NLPHL (n=18) | |
| Event free survival at 5 yrs | 61% (SE 12%) |
| Overall Survival at 5 years | 73% (SE 12%) |
| LCL (n=8) | |
| Event free survival at 5 yrs | 87% (SE 12%) |
| Overall Survival at 5 years | 87% (SE 12%) |
Although not supported by clinical trial data, patients with relapsed NLPHL are often treated with autologous transplant. Historically, two randomized trials have shown that patients with relapsed HL derive a significant benefit from autologous stem cell transplant over conventional therapy in regard to freedom from treatment failure, even amongst those with favorable disease characteristics.8, 13, 14 The lack of survival benefit has been attributed to the ultimate transplantation of those with relapsed disease initially assigned to the non-transplanted arm.7 Literature specifically looking at autologous transplantation in the setting of NLPHL is limited, and includes very few patients. Jackson et al. reported a median failure-free survival of 39.2 months (range 28.6–138.5 months) for NLPHL patients receiving autologous transplantation after achieving PR with standard chemotherapy. Five of 8 patients in their series experienced relapse after transplant and went on to receive further chemotherapy3. Basioli et al , reported 60% overall survival in 19 patients with NLPHL transformed to LCL. They demonstrated that 9 of 164 patients who received autologous transplantation for NLPHL transformed to large cell lymphoma had comparable OS to the 10 transformed patients who received salvage systemic therapies.4 Bierman et al reported on 19 patients treated with ASCT for relapsed or refractory NLPHL. Treatment outcomes were compared to 299 patients treated with ASCT for relapsed/refractory nodular sclerosing HL. Both progression free survival and OS were similar with a 5 year PFS following ASCT for patients with NLPHL of 50% compared to 39% of patients with nodular sclerosis HD (p=0.30), and a 5-year OS of 56% and 53%, respectively (p=0.36)15.
These results, along with our data, suggest that autologous transplantation is a potentially curative option for patients with relapsed NLPHL, particularly in the setting of chemosensitive disease. The low incidence rate of NLPHL precludes the development of prospectively designed randomized clinical trials evaluating the optimal therapeutic approach to this subset of patients. Aside from the limitations inherent to retrospective studies, the small number of patients available for review precluded the development of univariate or multivariate analysis to uncover specific patient characteristics predictive of outcome. The role of Rituximab as a part of the conditioning regimen in autologous transplantation also remains unanswered. Following suit with several other diseases, those with chemoresistant disease appear to be a higher risk for relapse following transplant. In summary, autologous transplantation is a reasonable therapeutic alternative for patients with relapsed or transformed NLPHL.
Figure 1. Overall and Event-free survival.
Footnotes
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Authorship Contributions
Contribution: M.K., C.H., U.P., designed the research and analyzed results; M.K., U.P., C.H., M.F., J.M., A.M.A., M.J.L, M.H.Q, P.K., A.Y., I.K., B.S.A, R.C., and P.A. wrote the paper.
Disclosure of Conflicts of Interest
The authors declare no competing financial interests.
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