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© 2001 American Society for Clinical Oncology Non-Hodgkin’s Lymphoma After Primary Hodgkin’s Disease in the German Hodgkin’s Lymphoma Study Group: Incidence, Treatment, and PrognosisFrom the First Department of Internal Medicine, University Hospital Cologne, Cologne, Germany. Address reprint requests to Ulrich Rüffer, MD, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str 9, 50924 Cologne, Germany; email: j-u.RUEFFER{at}uni-KOELN.DE
PURPOSE: The cumulative incidence for non-Hodgkin lymphoma’s (NHL) after primary Hodgkin’s disease (HD) ranges between 1% and 6%. To investigate the course of disease for secondary NHL, we retrospectively analyzed patients treated within clinical trials of the German Hodgkin’s Lymphoma Study Group (GHSG) since 1981. PATIENTS AND METHODS: From 1981 to 1998, the GHSG conducted three generations of clinical trials for the treatment of primary HD involving a total of 5,406 patients. Reference histology by an expert panel was obtained for 4,104 of the patients. Data on incidence, treatment, and outcome of secondary NHL were updated in March 1999. RESULTS: At first diagnosis of HD, the pathologists rejected 114 (2.1%) of 5,520 cases initially diagnosed as HD and rediagnosed them as primary NHL. Fifty-two (0.9%) of the remaining 5,406 patients developed a secondary NHL. One patient was excluded from further analyses because of insufficient documentation. Six patients had no further therapy because of patient refusal (n = 1) or rapidly progressive disease (n = 5). For the remaining 45 patients, overall response rate was 43% (36% complete response and 7% partial response). The actuarial 2-year freedom from treatment failure (FFTF) and overall survival (OS) for all patients was 24% and 30%, respectively, and for patients with diffuse large-cell lymphoma, it was 28% and 35%, respectively. Time of occurrence of secondary NHL after first diagnosis of HD and variables employed in the age-adjusted International Prognostic Factor Index (IPFI) significantly influenced treatment outcome. CONCLUSION: In the GHSG, the incidence of secondary NHL with 0.9% is relatively low compared with previously reported series. The prognosis of secondary NHL seems dismal and is significantly influenced by time of occurrence and the age-adjusted IPFI. In a subset of patients with secondary NHL, long-term disease-free survival could be achieved.
DEPENDING ON stage and risk factor profile, more than 80% of patients with Hodgkin’s disease (HD) can be cured with front-line treatment.1 However, long-term survivors of HD are at risk for late complications. Among these, secondary malignancies are the most serious because they are often fatal. The most widely reported secondary malignancies are solid tumors and acute leukemia.2-6 Less frequently, non-Hodgkin’s lymphomas (NHLs) have been described.7 The mechanism underlying the pathogenesis of NHL in HD patients remains to be clarified. Mutagenic effects of cytotoxic therapy, histologic conversion of HD, and defective immune surveillance have been considered.8 In several series, the incidence of NHL ranges from 1.0% to 5.9%.3 This variation might be explained by differences in observation time, infrequent use of rebiopsy at the time of disease progression or relapse, and the lack of a pathologist review panel. The majority of secondary NHL are intermediate or aggressive lymphomas of B-cell immunophenotype.9 Factors possibly contributing to the occurrence of secondary NHL are radiochemotherapy, older age, lymphocyte predominant histologic subtype, splenectomy, and spleen irradiation.7,10,11 Most authors reported that secondary NHL generally develops 5 to 15 years after treatment but might continue to occur with longer follow-up.3,4,5,6 Therapeutical strategies in second malignancies after HD are not standardized. Although the prognosis of secondary acute myeloid leukemia/acute lymphatic leukemia is extremely poor, several authors report persisting complete remissions after treatment for secondary solid tumors.3,4,5,6 However, treatment strategies and prognosis of secondary NHL are unknown. Thus, we retrospectively analyzed the database of the German Hodgkin’s Lymphoma Study Group (GHSG), including 5,406 patients, to determine the incidence, treatment, and prognostic factors of patients with secondary NHL in whom the diagnosis was confirmed by an expert panel of pathologists.
Between 1981 and 1999, 5,406 HD patients were enrolled onto various randomized trials of the GHSG. To be eligible, patients between the age of 16 and 75 years had to have biopsy-proven HD at diagnosis. Histology was subsequently reviewed by an expert pathologist panel in 4,104 cases (76%). At time of first diagnosis, the local pathologist was requested to send material to a member of the expert panel. Eligibility criteria before study entry included adequate organ function as defined by a creatinine clearance > 60 mL/min, serum transaminases less than three times normal, and bilirubin  2 mL/dL, left ventricular ejection fraction  0.45, forced expiratory volume in first-second or diffusion capacity of carbon monoxide > 60% of predicted, Karnofsky performance score of > 60, and WBCs 3,500/µL, hemoglobin level 8 g/dL, and platelets 100000/µL. With the start of the second study generation in 1988, patients were required to test negative for antibody against human immunodeficiency virus and to be free of active infections. All patients signed consent forms that were based on the institutional review board guidelines. Time schedule, trial designs of the different study generations, and the number of enrolled patients are listed in Table 1.
As at first diagnosis, histology of secondary NHL was confirmed by an expert pathologist panel. Data to be included for analysis of prognostic factors for secondary NHL consisted of age, B symptoms, clinical stage according to Ann Arbor classification, Karnofsky performance score, lactate dehydrogenase (LDH) level, time between primary HD and secondary NHL, type of treatment regimen for HD including chemotherapy, radiotherapy, combined modality treatment, or high-dose chemotherapy (HDCT) with stem-cell transplantation. Treatment decision for secondary NHL was made by the attending physician. Regimens used were cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP), etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B), doxorubicin, cyclophosphamide, vincristine, methotrexate, ifosfamide, tenoposide, cytarabin, and dexamethasone (B-ALL), dexamethasone, carmustine, etoposide, cytarabin, melphalan (Dexa-BEAM), methotrexate, ifosfamide, and etoposide (IMVP16), ifosfamide, etoposide, idarubicin, and dexamethasone (DIIVP16), dexamethasone, cytarabin, and cisplatinum (DHAP), and cyclophosphamide, vincristine, and prednisone (COP). The data analysis employed survival data of all patients recorded in the GHSG trial database as of March 1999.
Staging Procedures at Diagnosis of Secondary NHL
Response Definition
Statistics
Patient Characteristics Patient characteristics are listed in Table 2. We identified 52 patients with a secondary NHL from the database of the GHSG. One patient was excluded from the final analysis for treatment outcome because of lack of information. At the time of first diagnosis of HD, the median age of the patients was 47 years (range, 19 to 71 years). There were 41 males (80%) and 10 females (20%) with the following histologies at HD diagnosis: nodular sclerosis, n = 19 (37%); mixed cellularity, n = 19 (37%); lymphocyte depleted, n = 2 (4%); lymphocyte predominant, n = 8 (16%), and nonclassified, n = 3 (6%). Twenty patients (39%) had early/intermediate stage, and 31 patients (61%) had advanced stage at first diagnosis of HD. Primary treatment for HD consisted of radiotherapy alone in eight patients (16%), chemotherapy alone in 21 patients (41%), and combined modality in 22 patients (43%). From those, 11 patients experienced a relapse of HD, which was treated in two patients with HDCT and autologous stem-cell transplantation.
At the time of diagnosis of secondary NHL, the median age was 49 years (range, 19 to 74 years). Stage at secondary NHL by Ann Arbor criteria was stage I in 11 patients (22%), stage II in 17 (33%), stage III in three (6%), and stage IV in 20 patients (39%). Twenty-five patients (49%) had a Karnofsky performance score of more than 90. The median LDH level was 261 U/L (range, 106 to 3000 U/L). Twelve patients (24%) had only nodal involvement, 23 patients (45%) had extranodal disease, eight patients (30%) extranodal disease and organ involvement, and seven patients (14%) only organ involvement. Sites of involvement are listed in Table 3. At diagnosis of secondary NHL, the patients were found to have the following histologies according to the Revised European-American Lymphoma (REAL) classification: diffuse large B-cell lymphoma, n = 40 (78%); precursor B-cell lymphoblastic lymphoma, n = 1 (2%); follicular center lymphoma, n = 2 (4%); marginal-zone B-cell lymphoma, n = 1 (2%); and T-cell NHL, n = 7 patients (14%). These histologies were confirmed by an expert panel of lymphoma pathologists in 82% of cases. Assignment to the REAL classification was performed without reassessment by current diagnostic procedures.
Results of the Pathologist Expert Panel At first diagnosis of HD from 5,520 cases, the expert panel of pathologists reviewed the histology of 4,104 patients. From these, they rejected 114 cases initially diagnosed as HD and rediagnosed them as primary NHL, representing 2.1% of all patients. Thus, 5,406 patients were randomized.
Time of Occurrence and Relative Risk of Secondary NHL
Response to Treatment of Secondary NHL The treatment regimens used and response rates for secondary NHL are listed in Table 4. Six patients (12%) received no further therapy due to rapid disease progression. These patients developed secondary NHL while being treated for HD. Histology in all cases was diffuse large B-cell lymphoma. Of the 45 patients treated for secondary NHL, 24 (47%) received chemotherapy alone, eight (15%) received radiotherapy alone, six (13%) received combined-modality treatment, and five (9%) patients were treated with HDCT followed by autologous (two patients) or allogeneic (three patients) stem-cell transplantation. Two patients with cutaneous peripheral T-cell lymphomas were treated with psoralen + ultraviolet A and interferon gamma.
The overall response rate was 43% (36% CR and 7% PR). Response and outcome for patients with T-cell lymphoma, low-grade B-cell lymphoma, and precursor B-cell lymphoblastic Lymphoma are listed separately in Table 5.
Survival Data With a median follow-up of 26 months for all patients with secondary NHL, the actuarial FFTF at 2 years was 24% and the actuarial OS at 2 years was 30% ( Fig 2). For patients with diffuse large-cell lymphoma, the 2-year OS and FFTF were 28% and 35%, respectively. OS and FFTF at 2 years for the 21 patients with diffuse large-cell lymphoma treated with a doxorubicin-containing regimen were 50% and 54%, respectively ( Fig 4). Data for OS and FFTF of other entities are listed in Table 5 for each patient.
Prognostic Factors for SV and FFTF After Secondary NHL In the univariate analysis, time of occurrence (< 12 months v 12 months) after first diagnosis of HD was a significant prognostic variable associated with FFTF and OS ( Fig 3). Prior treatment for HD had no significant influence on FFTF and OS. All 51 patients were grouped by risk factor as defined by the age-adjusted IPFI. There were 16 patients in the low-risk, 13 in the low-intermediate, 10 in the high-intermediate, and four in the high-risk group. FFTF was significantly (P = .03) better for patients in the low or low-intermediate risk group. OS showed no significant difference.
The following findings emerge from this analysis: (1) Compared to previous reports, a notably lower incidence of secondary NHL was observed in the entire cohort of the GHSG. It seems reasonable to suppose that the constitution of an expert pathologist panel detecting several NHL first diagnosed as HD explains this low incidence. (2) Diffuse large B-cell lymphoma was the main histology subtype, to be found presenting with a more extranodal (61%) involvement than reported in primary diagnosed NHL (30%). (3) In approximately 20% of patients with secondary NHL, long-term disease-free survival could be achieved. (4) Finally, the treatment outcome of secondary NHL was influenced by the time of occurrence after first diagnosis of HD and variables included in the age-adjusted IPFI. Although there are several reports about the incidence and risk factors for developing a secondary NHL after primary HD, little is known about treatment outcome and prognostic factors of these patients. Several authors have reported poor outcome after the diagnosis of secondary NHL. More recent data, however, suggest that these patients can be cured with aggressive multi-agent chemotherapy. Zarate-Osorno et al14 reported on 14 cases of secondary NHL, which were not treated in a uniform manner. Complete remission was achieved in seven patients. Five patients were alive without disease after a mean of 3.1 years. Two smaller series reported that more than half of their patients were effectively treated, but longer follow-up is needed to assess final outcome.15,16 In our analysis, the 2-year FFTF and OS for all patients were 24% and 30%, respectively. Patients with diffuse large B-cell lymphoma showed a 2-year FFTF of 28% and an OS of 35%. Patients with secondary T-cell lymphoma had a poor outcome with six of seven patients dying between 3 and 28 months after diagnosis. Thus, prognosis of secondary diffuse large B-cell lymphoma is worse than reported for primary lymphomas, whereas the occurrence of secondary T-cell lymphoma seems to be fatal. The outcome was significantly influenced by the time of occurrence after HD and variables of the age-adjusted IPFI. Patients developing a secondary NHL within 3 months after the end of first-line treatment for HD had an OS of 20% versus 42% for patients developing a secondary NHL after 12 months. Thus, regarding prognosis, patients with an early occurrence of secondary NHL are comparable with patients with primary progressive HD. The prognosis might be poor due to an aggressive course of disease of a primary composite lymphoma not detected at diagnosis of HD, alternatively HD therapy may comprise further treatment strategies. This latter hypothesis is supported by the data on OS and FFTF for patients with diffuse large B-cell lymphoma receiving a doxorubicin-containing regimen. Patients for whom the application of a standard chemotherapy was not restricted by primary therapy for HD or their Karnofsky index had considerably better prognosis. Although the age-adjusted IPFI was validated for primary, rather than secondary, NHL, patients belonging to the high/high-intermediate risk group or low/low-intermediate risk group had a 2-year FFTF of less than 10% and 40%, respectively. Whereas patients with primary NHL belonging to the high-risk group are now considered for dose-intensified treatment strategies, those concepts are compromised in secondary NHL due to the poor performance status and previous HD therapy. In conclusion, palliative treatment strategies may be more appropriate for patients with high-risk secondary NHL. Because this analysis is performed retrospectively and the IPFI is not validated for secondary NHL, these results have to be confirmed in larger series. In smaller series reported from other groups, the cumulative incidence of secondary NHL ranges from 1.0% to 5.9% but might increase with longer follow-up.17,18,19 Some groups reported that the risk of secondary NHL remained constant during the follow-up period,20 whereas others observed the greatest risk beginning from 10 years after first-line treatment.5,18,19 In our series, the incidence of secondary NHL remained fairly constant from 0 to 8 years. These differences might be explained by infrequent use of rebiopsy at second events in other series, especially in progressive disease/early relapses, the lack of a pathologist review panel, and the different observation times. From a total of 256 patients enrolled in clinical trials of the GHSG who developed progressive disease, a rebiopsy was available in only 57%. Of the 147 patients with a rebiopsy, 12 (8%) were found to have a secondary NHL.21 Furthermore, our analysis is one of the few in which the bias of misdiagnosis of the primary NHL tumor as HD is diminished. At first diagnosis of HD, the expert panel of pathologists rejected 114 cases initially diagnosed as HD and rediagnosed them as primary NHL representing 2.1% of all patients. In addition, our results show that a high percentage of secondary NHL developing in HD patients were of the B-cell immunophenotype and that the majority of patients presented with diffuse large B-cell lymphoma. As has been reported by others, many of these patients presented with extranodal sites.8 In conclusion, whereas secondary NHL patients with favorable prognostic features can be cured with multiagent chemotherapy regimens, our analysis suggests a palliative treatment approach for those with unfavorable subtypes. In future trials, an expert panel of pathologists and rebiopsy at disease progression or relapse are warranted to avoid misdiagnosis of primary NHL as HD and to allow an effective assessment of the incidence of secondary NHL.
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Enrici RM, Anselmo AP, Iacari V, et al: The risk of non-Hodgkin’s lymphoma after Hodgkin’s disease, with special reference to splenic treatment. Haematologica 83: 636-644, 1998 8. Bennett MH, MacLennan KA, Vaughan Hudson G, et al: Non-Hodgkin’s lymphoma arising in patients treated for Hodgkin’s disease in the BNLI: A 20-year experience. Ann Oncol 2: 83-92, 1991 (suppl 2) 9. Amini RM, Enblad G, Sundström C, et al: Patients suffering from both Hodgkin’s disease and non-Hodgkin’s lymphoma: A clinico-pathological and immuno-histochemical population-based study of 32 patients. Int J Cancer 71: 510-516, 1997[Medline] 10. Biti G, Cellai E, Magrini S, et al: Second solid tumors and leukemia after treatment for Hodgkin’s disease: An analysis of 1121 patients from a single institution. Int J Radiat Oncol Biol Phys 29: 25-31, 1994[Medline]
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Shipp MA: A predictive model for aggressive Non Hodgkin’s lymphoma: The International Non Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329: 987-994, 1993 14. Zarate-Osorno A, Medeiros LJ, Longo DL, et al: Non Hodgkin’s lymphoma arising in patients successfully treated for Hodgkin’s disease: A clinical, histologic, and immunophenotypic study of 14 cases. Am J Surg Pathol 16: 885-893, 1992[Medline]
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Henry-Amar M, Joly F: Late complications after Hodgkin’s disease. Ann Oncol 7: 115-126, 1996 (suppl 4) 18. Robinson E, Bar-Deroma R, Epelbaum R, et al: Clinical characteristics of non-Hodgkin’s lymphoma as a second primary tumor: A population-based survey. Leuk Lymphoma 20: 297-301, 1996[Medline] 19. Van Leeuwen FE, Somers R, Taal BG, et al: Increased risk of lung cancer, non-Hodgkin’s lymphoma, and leukemia following Hodgkin’s disease. J Clin Oncol 7: 1046-1058, 1989[Abstract] 20. Swerdlow AJ, Douglas AJ, Hudson JV: Risk of second primary cancer after Hodgkin’s disease by type of treatment: Analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304: 1137-1143, 1992
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
