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© 2002 American Society for Clinical Oncology Intensive Salvage Therapy With High-Dose Chemotherapy for Patients With Advanced Hodgkin’s Disease in Relapse or Failure After Initial Chemotherapy: Results of the Groupe d’Études des Lymphomes de l’Adulte H89 TrialByFrom the Groupe d’Études des Lymphomes de l’Adulte, Hôpital Saint-Louis, Paris; Department of Biostatistics and Medical Information Systems, Hôpital Henri Mondor, Créteil; Centre Henri Becquerel, Rouen; Centre Hospitalier Universitaire, Caen; Centre Hospitalier Universitaire, Besançon; Centre Hospitalier Régional, Clermont-Ferrand; Centre Hospitalier Universitaire, Vandoeuvre; Polyclinique Courlancy, Reims; Hôpital Edouard Herriot, Lyon; and Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. Address reprint requests to Christophe Fermé, MD, Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; email: ferme{at}igr.fr
PURPOSE: To evaluate prospectively the feasibility and efficacy of early intensive therapy, including intensified cytoreductive chemotherapy (CT) and high-dose CT (HDCT) followed by autologous stem-cell transplantation (ASCT), in patients with advanced Hodgkin’s disease (HD) who failed to respond completely or relapsed after initial treatment. PATIENTS AND METHODS: Among 533 eligible patients with newly diagnosed stage IIIB-IV HD enrolled in the H89 trial, all 157 patients with induction failure (IF) (n = 67), partial response (PR) of less than 75% (n = 22), or relapse (n = 68) were included in this study. Planned salvage therapy included mitoguazone, ifosfamide, vinorelbine, and etoposide monthly for two to three cycles followed by high-dose carmustine, etoposide, cytarabine, and melphalan with ASCT. RESULTS: With a median follow-up of 50 months, the 5-year survival estimates were 30%, 72%, and 76% for the IF, PR, and relapse groups, respectively (P = .0001), 71% for the 101 patients given HDCT, and 32% for the 48 patients treated without HDCT (P = .0001). Multivariate analysis using time-dependent Cox model indicated that B symptoms at progression, salvage without HDCT, and chemoresistant disease before HDCT were significantly associated with shorter overall survival. CONCLUSION: Early intensive therapy improves the outcomes of patients with advanced HD who failed to respond completely to initial treatment and those who relapsed with adverse prognostic factors. However, for patients with IF and chemoresistant disease, this approach remains unsatisfactory.
MOST PATIENTS WITH advanced Hodgkin’s disease (HD) can be cured with the use of chemotherapy (CT) combined or not with radiation therapy (RT). However, 30% to 50% of these patients experience disease progression during initial therapy or relapse after achieving remission.1,2 High-dose CT (HDCT) followed by hematopoietic stem-cell transplantation has obtained sustained remissions in patients with advanced refractory or recurrent HD, as reported in retrospective series.3-10 However, only a few studies have prospectively evaluated the role of high-dose therapy in this setting.11,12 Response to first-line conventional CT has been shown to constitute a good predictor of outcome, and early restaging may help identify poor responders to such therapy.13 The use of HDCT with autologous stem-cell transplantation (ASCT) as an integrated part of front-line treatment might then be a strategy to cure patients who fail to achieve complete remission (CR) or good partial response (PR) to initial CT. To address this possibility, in 1989, the GELA integrated intensive salvage therapy into the H89 trial for patients who had failed to respond completely or relapsed after initial treatment. Such an approach was applied to high-risk patients who were studied prospectively. We report herein the feasibility and efficacy of salvage therapy including intensified cytoreductive CT and HDCT.
Patients In 1989, the Groupe d’Études des Lymphomes de l’Adulte (GELA) initiated a prospective multicenter trial, designated H89, for patients with newly diagnosed HD and classified as being Ann Arbor stage IIIB-IV.14 The primary objective of the H89 trial was to compare, for patients who had achieved a CR or PR of at least 75% after six cycles of induction CT, two consolidation treatment procedures consisting of either two additional cycles of CT or RT ([sub]total nodal irradiation). The main secondary objective was to treat patients with a response of less than 75%, progressive HD after induction CT, or relapse with HDCT. The patients were 15 to 65 years old at the time of HD diagnosis. They were enrolled between July 1989 and December 1996 at 60 participating centers (Appendix). Informed consent was obtained from every patient before enrollment. Evaluation of responses after four and six cycles of induction CT and at completion of consolidation CT or RT have been described previously.14 Patients were considered to have IF when they met one of the following criteria: disease regression of less than 50% after four to six cycles of CT, histologic evidence of bone-marrow involvement after four cycles of CT, progressive disease defined as an increase of tumor size or evidence of new sites of involvement, temporary PR followed by progression under treatment or within 1 month after the completion of initial treatment. Partial response was defined as a reduction of 50% to less than 75% in the largest diameter of each measurable site. Relapse was defined as disease progression occurring more than 1 month after the completion of initial treatment in patients who had entered CR. A total of 533 patients were eligible for the H89 trial, and the study population at the time of this analysis consisted of 157 patients who fulfilled the criteria of IF (n = 67), PR (n = 22), or relapse (n = 68).
Treatment Patients were eligible to receive HDCT when they were under 61 years old, had adequate cardiac, pulmonary, hepatic, and renal functions, and had no disease progression after cytoreductive CT. The conditioning regimen consisted of carmustine, etoposide, cytarabine, and melphalan (BEAM), followed by ASCT. RT was indicated for residual masses and was delivered after HDCT to patients not previously irradiated. The BEAM regimen consisted of carmustine 300 mg/m2 IV for 1 hour on day -6; etoposide 200 mg/m2 (100 mg/m2 IV for 1 hour twice daily) on days -5, -4, -3, and -2; cytarabine 200 mg/m2 (100 mg/m2 IV for 1 hour twice daily) on days -5, -4, -3, and -2; and melphalan 140 mg/m2 IV for 1 hour on day -1. When the study was initiated, hematopoietic progenitor cells were collected according to institutional protocols, autologous bone-marrow, peripheral-blood stem cells, or both. After August 1995, bone marrow was no longer collected. Hematopoietic progenitor cells were collected after mobilization using the MINE regimen. Hematopoietic growth factor, stem-cell cryopreservation, colony assay techniques, and supportive care were used according to the protocol at each participating center. Response was evaluated at least 1 month after completion of treatment. Patients with small residual radiographic abnormalities that did not progress for 6 months after salvage therapy were classified as having attained CR. When the assigned treatment had failed or had been considered not feasible, other treatments were allowed at the discretion of the treating physician, including cytoreductive CT without HDCT or conventional combination CT, preceding or not preceding RT.
Statistical Analyses Survival was calculated from the time of the first randomization (induction treatment) to the stopping date, date of death, or date of last follow-up evaluation when the stopping date had not yet been reached. Duration of freedom from second failure (FF2F) was measured from the date of progression or first relapse to the stopping date, toxic death, second relapse, or last follow-up when the stopping date had not yet been reached. When less than a CR was obtained after salvage treatment for first failure or relapse, the duration of FF2F was considered to be zero. Survival was estimated using the Kaplan-Meier method,18 and univariate analyses were performed using the two-sided log-rank test.19 Because HDCT was not randomly assigned, we controlled for the effects of various prognostic factors on outcome because of sampling fluctuation in the treatment groups by means of multivariate analysis of survival. Potential prognostic factors for survival after failure or relapse were risk factors adapted from the Vancouver model (time from the start of induction treatment to failure/PR or initial duration of remission for CR, extranodal disease, and B symptoms at progression)7 and responses to cytoreductive CT (chemosensitive or chemoresistant) and salvage therapy with or without HDCT. However, to undergo HDCT, a patient had to survive long enough to achieve a tumor response; thus HDCT, tumor response, and timing had to be taken into account to avoid a time-to-transplant bias. When considering a standard multivariate approach with time-fixed treatment of the HDCT covariate,20 the time of HDCT is erroneously projected back to baseline, leading to artificially stratified groups of transplanted and nontransplanted patients at time t = 0, without respecting the actual HDCT time. To avoid this type of bias in favor of the HDCT group, we used the time-dependent Cox regression model approach with switch variables (for example, HDCT coded at baseline as not transplanted for all patients could be switched to transplanted at different times during follow-up for some patients).21 The switch-variable response, which is associated with the time lapse to an objective tumor response, was considered a second time-dependent covariate. All other covariates were fixed. All statistical analyses were carried out using SAS 6.12 software (SAS Institute, Cary, NC).
Patient Characteristics The characteristics of the patients at the time of HD diagnosis are listed in Table 1. The median age was 32 years (range, 15 to 65 years). There were 96 men and 61 women. According to the international prognostic score for advanced HD,22 96% of the patients had a score of  2, including 90% with a score of 3% and 63% with a score of 4. A schematic breakdown of patients according to their initial treatment is given in Fig 1. One hundred twenty patients had initially received CT alone (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine [MOPP/ABV] hybrid23 or doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone [ABVPP]. Thirty-seven patients had been treated with CT plus consolidation RT delivered to mantle field, paraaortic, and spleen areas in 13 patients and mantle field, inverted Y, and spleen areas in 12 patients; and the planned volumes of RT were partially delivered in 12 patients.
The diagnoses of IF and PR were based on the following: biopsy-proven HD in 32 patients (36%), clinical and/or radiologic evidence of persistent disease in 51 patients (57%), and positive gallium scan for six patients (7%). Relapse was documented by biopsy in 44 patients (65%). Otherwise, unequivocal new imaging lesions (19 radiologic and five gallium scan lesions) were accepted as proof of relapse in the absence of another explanation. The patient characteristics at the time of IF, PR, or relapse are listed in Table 1, and the relapse patterns are listed in Table 2. Among the 68 patients who relapsed, the median duration of the first CR was 15 months (range, 1 to 9 months), and 29 patients (43%) relapsed within 12 months after achieving that CR. The recurrence rate within the irradiated fields was 8% (16 nodal relapses out of 195 patients at risk).
The distribution of the patients according to salvage therapy is detailed in Fig 2, and alternative treatments to cytoreductive CT with MINE and HDCT with BEAM are listed in Table 3. Eighty-three patients (53%) received the MINE regimen for a median number of two cycles. Of these patients, seven received one cycle, 39 received two cycles, 25 received three cycles, 10 received four cycles, and two received five cycles of MINE. Sixty-four patients (41%) received a cytoreductive CT other than the MINE regimen, either intensified CT (ifosfamide, etoposide, and doxorubicin, n = 25; other salvage regimen, n = 12) or conventional combination CT (n = 27). Two patients received only RT. Another eight patients did not receive any treatment because of rapidly progressive disease. A total of 101 patients (64%) received HDCT; 69 of them (68%) received the planned preparative BEAM regimen. Twenty-nine patients received another conditioning regimen for the following reasons: medical decision (n = 18) and tandem HDCT (including 12-Gy total-body irradiation, n = 5) for 11 patients with IF as part of a phase II study.24 Three other patients received a conditioning regimen with HDCT and total-body irradiation followed by allogeneic bone-marrow transplantation. Posttransplantation RT, 20 to 40 Gy, was given to 31 patients (17 mantle field, seven mediastinum, three subtotal nodal irradiation, two total nodal irradiation, and two subdiaphragmatic). Finally, a total of 50 patients received the planned MINE cytoreductive CT followed by HDCT with BEAM. The sources of autologous progenitor cells were peripheral-blood stem cells for 85 patients, bone marrow for nine patients, and both for four patients. The remaining 48 patients received salvage therapy without HDCT for the following reasons: failure to respond to cytoreductive CT (n = 19), patient refusal (n = 7), protocol violation (n = 8), age 60 years old (n = 6), organ failure or poor performance status (n = 3), treatment-related death (n = 4), and failure to harvest an adequate number of hematopoietic stem cells (n = 1).
Response to Salvage Therapy The numbers of patients with chemosensitive disease and patients who achieved CR after salvage therapy are listed in Table 3, and results of salvage therapy for all patients are listed in Table 4. After cytoreductive CT, 40 of the 64 patients with IF and 73 of the 83 patients with PR or relapse were restaged as having chemosensitive disease. Response rates after MINE, other intensified CT, or conventional-dose CT were 75%, 81%, and 77%, respectively. Among the 50 patients who had received the planned treatment, 45 (90%) were restaged as having chemosensitive disease after MINE, and 42 (84%) achieved CR after BEAM. Among the 51 patients who had received alternative treatments including HDCT, 44 patients (86%) had chemosensitive disease, and 38 patients (75%) achieved CR after salvage therapy. Overall, 12 patients had disease chemoresistant to cytoreductive CT, and 89 patients had chemosensitive disease before HDCT; 80 of these 89 patients achieved CR after HDCT. Among these 89 patients with disease chemosensitive to cytoreductive CT, 66 out of 70 CR or good PR patients and 11 out of 19 PR patients achieved CR after HDCT (P = .001). Among the three patients treated with allogeneic bone marrow transplantation, two failed to respond to salvage therapy and died of veno-occlusive disease, and one patient entered CR and remains disease free (36 months).
Overall Survival The median follow-up from HD diagnosis was 50 months (range, 8 to 105 months). At the stopping date, 65 patients (41%) had died, 43 in the IF group, six with a PR, and 16 who relapsed. Forty-five patients (69%) died of HD progression; nine (14%) died of treatment-related complications during first-line treatment (n = 2) or subsequent salvage therapy (n = 7), and seven of these nine patients had had persistent HD. Eight other deaths were caused by a second cancer (solid tumor, n = 4; non-Hodgkin’s lymphoma, n = 3; and acute leukemia, n = 1). Intercurrent causes of death were as follows: cerebral hemorrhage with HD progression, n = 1; and unknown with persistent HD, n = 2. The 5-year survival estimate for all patients was 56% (95% confidence interval [CI], 48% to 64%). The 5-year survival estimates for the three subgroups of patients were 30% (95% CI, 16% to 44%) for the IF group, 72% (95% CI, 54% to 90%) for those with PR, and 76% (95% CI, 66% to 86%) for those who relapsed (P = .0001) (Fig 3). The 5-year survival estimate was 71% (95% CI, 61% to 81%) for the 101 patients treated with HDCT and 32% (95% CI, 18% to 46%) for the 48 patients treated without HDCT, including 21 patients with IF (P = .0001) (Fig 4). The 5-year survival estimates according to response to cytoreductive CT before HDCT were 72% (95% CI, 62% to 82%) for the patients with chemosensitive disease and 13% (95% CI, 1% to 25%) for those with chemoresistant disease (P = .0001). Among patients with disease chemosensitive to cytoreductive CT, the 5-year survival estimates according to response before HDCT were 86% (95% CI, 76% to 96%) for the patients with CR or good PR and 37% (95% CI, 7% to 67%) for those with PR of less than 75% (P = .0001). The 5-year survival estimate was 89% (95% CI, 81% to 97%) for the 94 patients who achieved CR after salvage therapy. First-line consolidation treatment had no significant effect on survival of relapsed patients (log-rank P = .18, from a Kaplan-Meier analysis of overall survival after relapse).
FF2F The actuarial FF2F for the entire population was 46% (95% CI, 38% to 54%). The 5-year FF2F estimates for the three subgroups of patients were 23% (95% CI, 13% to 33%) for IF, 66% (95% CI, 56% to 76%) for patients with a PR, and 67% (95% CI, 53% to 81%) for those who relapsed (P = .0001) (Fig 3). The 5-year FF2F estimate was 60% (95% CI, 50% to 70%) for the 101 patients treated with HDCT and 20% (95% CI, 4% to 36%) for the 48 patients who were treated without HDCT (P = .0001). The 5-year FF2F estimates for the 89 patients with chemosensitive disease after cytoreductive CT before HDCT and the 12 patients with chemoresistant disease were 64% (95% CI, 52% to 76%) and 25% (95% CI, 1% to 49%), respectively (P = .0001).
Multivariate Analysis
The results of this study indicate that early intensive therapy improves the outcomes of patients with advanced HD who failed to respond completely after initial treatment or who relapsed. The benefit of HDCT is supported by the multivariate analysis using the time-dependent model. Unfortunately, the overall survival estimate for the IF group remains unsatisfactory. The study population included high-risk patients, with 57% of them having failed to achieve CR or good PR after initial treatment and 18% having relapsed after an initial remission of less than 12 months’ duration. Other risk factors, such as systemic symptoms and extranodal disease at progression, were at least as frequent as in other studies.7,10 All the patients had received only one treatment regimen before salvage therapy, and a combined modality had been used in 17% of the patients with IF or PR and 32% of relapsed patients. Because we prospectively studied patients enrolled onto the H89 trial, their treatment before salvage therapy had been homogeneous, unlike other studies.8,12 The percentage of patients in this population who failed to enter CR or obtain good PR after induction CT is consistent with other series of advanced HD patients treated with doxorubicin-containing regimens.1,2 Because progression after CR lasting only 1 month was defined as a relapse, nine of our patients who relapsed within 3 months would have been considered as having primary progressive disease according to the criteria of other series.25,26 In the H89 trial, intensive salvage therapy was an integral part of the planned treatment for patients with IF, PR of less than 75%, or relapse. In an attempt to obtain minimal residual disease, to identify early patients with chemosensitive disease,12 and to reduce the length of treatment before HDCT, we preferred intensified cytoreductive CT to conventional CT.7,8 In our study, 32% of the patients received the planned treatment (MINE-BEAM-ASCT), 53% received the MINE regimen as part of salvage therapy, and 62% were treated with HDCT. Our results illustrate the difficulty of a prospective and multicenter study of HDCT as salvage therapy, with about two thirds of the patients receiving HDCT and the other patients being either treated without HDCT (31%) or left untreated (5%) for reasons defined in the protocol, primarily disease progression during cytoreductive CT. Although selection bias existed for patients receiving HDCT, 61% of our patients with IF received HDCT compared with 34% of patients with primary progressive HD analyzed retrospectively by the German Hodgkin’s Lymphoma Study group.26 In our study, because of the low number of patients receiving conventional-dose CT before HDCT (n = 8) and the selection bias for intensive cytoreductive CT, no conclusion can be drawn as to the best treatment before HDCT. Salvage therapy for advanced-stage HD patients who fail or relapse after a doxorubicin-containing regimen has been widely investigated.3-10,27-30 Our prospective study helps to define the role of HDCT in these circumstances. Patients in first relapse experienced favorable outcomes after intensive salvage therapy, with a 5-year FF2F rate of 67%. These results are consistent with the benefit of HDCT for advanced-stage HD in first relapse with unfavorable prognostic factors7-10 and confirm our previous experience with the MINE regimen for untreated relapses.17 However, a longer follow-up is needed to assess adequately the important issues of tumor control and toxicity.31 Favorable outcomes for patients who achieved PR of less than 75% after induction CT, with a 5-year FF2F estimate of 66%, support a similar approach for patients with evidence of persistent disease at early restaging. However, the low number of patients in this group does not permit a definitive conclusion at this time. The benefit of early HDCT for advanced HD patients achieving PR after induction therapy is still controversial. In some institutions, partial responders are not considered candidates for HDCT until disease progression and are routinely observed.2,30 The encouraging results of early intensive therapy with ASCT in a pilot study32 and retrospective analysis33 provide strong arguments for conducting prospective studies comparing HDCT to conventional treatment for high-risk advanced HD responding to CT. In contrast, IF patients had poor outcomes, with a 5-year FF2F rate of 23%, despite an overall response rate to cytoreductive CT of 62% and the administration of HDCT to two thirds (64%) of the patients. IF predicts poor control with HDCT, regardless of apparent CR and response to cytoreductive CT, although those patients did not respond as well to salvage therapy as patients in PR or relapse. This outcome may be explained by the unfavorable characteristics and the chemoresistance of the disease in these patients. Outcome of IF patients given further conventional therapy is extremely poor.25 HDCT has been considered the best available therapy for this subset of patients.34 However, our results show that only a small portion of IF patients may be cured with HDCT. Also, the results from other recent series26 show that this therapy is not yet optimal. In an attempt to analyze further the patients’ outcomes, taking into account our strategy of intensive cytoreductive CT and HDCT, a multivariate survival analysis was performed including the Vancouver risk factors, response to cytoreductive CT, and salvage therapy (with or without HDCT). Although results of unplanned analyses must be interpreted with caution,35 multivariate analysis suggested that HDCT might improve the outcome of patients responding to cytoreductive CT, without significant interactions between response and prognostic factors. Therefore, the good outcomes of the HDCT patients may be a result of patient selection, particularly response to cytoreductive CT. This point was made in recent retrospective analyses of patients with primary progressive HD.26,36 In our prospective but not randomized study, this selection bias could not be avoided; however, the time-dependent Cox regression model approach was chosen to reduce the bias in favor of the HDCT group. The poor outcome of patients with IF, even with early intensified therapies, emphasizes the need to investigate new treatment strategies. Salvage treatment is of major importance to obtain high response rates with minimal tumor burden before HDCT for patients with chemosensitive disease. The early identification of patients at high risk and the evaluation of more effective cytoreductive CT regimens are needed to better define patients who might benefit from HDCT and those for whom new therapeutic options or palliative treatments should be used. Intensified CT followed by double HDCT and allogeneic bone-marrow minitransplantations could be alternative approaches. In an attempt to define a risk-adapted strategy and to conduct clinical trials, prognostic factors at progression and response to salvage CT remain important. The French Society of Bone Marrow Transplant and GELA are currently conducting a phase II trial including intensified cytoreductive CT followed by tandem HDCT for patients with IF or relapses with more than one risk factor, and intensified cytoreductive CT followed by single HDCT for first relapses with one adverse prognostic factor.
APPENDIX
We thank Fabrice Jehanno for assistance with data management and Janet Jacobson for editing our English.
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Josting A, Reiser M, Rueffer U, et al: Treatment of primary progressive Hodgkin’s and aggressive non-Hodgkin’s lymphoma: Is there a chance for cure? J Clin Oncol 18: 332–339, 2000 Submitted August 12, 2000; accepted August 29, 2001. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
