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High-Dose Therapy and Autologous Stem-Cell Transplantation for Adult Patients With Hodgkin's Disease Who Do Not Enter Remission After Induction Chemotherapy: Results in 175 Patients Reported to the European Group for Blood and Marrow Transplantation

From the CRC Wessex Medical Oncology Unit, University of Southampton, Southampton; Department of Clinical Haematology, University College Hospital, and Royal Marsden Hospital, London; Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom; Ematologia Ed Autotrapianto di Midollo, Ospedale S Martino, Genova, and Centro Trapianti di Midollo, Ospedale Maggiore di Milano, Milan, Italy; and Second Department of Internal Medicine, Christian Albrechts University, Kiel, Germany.

Address reprint requests to John Sweetenham, MD, CRC Wessex Medical Oncology Unit, University of Southampton, Southampton General Hospital, Tremona Road Southampton SO16 6YD, United Kingdom; email jws{at}soton.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To investigate the results of high-dose therapy and autologous stem-cell transplantation (ASCT) in adults with Hodgkin's disease who do not enter remission after induction therapy, to determine overall survival (OS) and progression free survival (PFS), and to identify prognostic factors.

PATIENTS AND METHODS: A retrospective analysis of 175 patients reported to the European Group for Blood and Marrow Transplantation between November 1979 and October 1995. One hundred were male and 75 were female, with a median age of 26.5 years. Responses to first-line therapy were defined as progressive disease (PD) in 88 and stable/minimally responsive disease (SD/MR) in 87. Seventy-five patients received ASCT after failure of one induction regimen. Second-line therapy was given to the remaining 100 patients. Response to second-line therapy was PD in 34 and SD/MR in 66. OS and PFS rates were determined, and prognostic factors were investigated using univariate and multivariate analyses.

RESULTS: Responses to high-dose therapy and ASCT were complete response (30%), partial response (28%), no response (14%), PD (14%), and toxic death (14%). Actuarial 5-year OS and PFS rates were 36% and 32%, respectively. In univariate analysis for PFS and OS, adverse factors were use of a second-line chemotherapy regimen and interval of more than 18 months between diagnosis and ASCT. In multivariate analysis, the interval between diagnosis and ASCT maintained prognostic significance for OS. Response to the chemotherapy regimen given immediately before ASCT had no predictive value.

CONCLUSION: High-dose therapy and ASCT is an effective treatment strategy for patients with Hodgkin's disease for whom induction chemotherapy fails. Outcome was equivalent for those with obvious PD or SD/MR in response to the regimen given immediately before high-dose therapy. Prospective randomized studies are required to compare this approach with conventional-dose salvage therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE USE OF MODERN combination chemotherapy regimens in advanced Hodgkin's disease produces complete remission rates of 70% to 80%, with long-term disease-free survival in 60% to 70% of patients.^1-4 However, the outcome for patients for whom initial induction chemotherapy fails is poor. The use of conventional-dose, second-line chemotherapy produces low remission rates, with long-term disease-free survival in only 10% to 15% of patients.^5,6

High-dose therapy with autologous stem-cell transplantation (ASCT) has been tested extensively in patients with relapsed and refractory Hodgkin's disease in recent years. Patients with primary refractory disease have been included in several reported series from single institutions.^7-17 Most of these reports have demonstrated that 20% to 30% of patients with primary refractory disease may achieve long-term disease-free survival after high-dose therapy. However, none of the published series have specifically addressed this group of patients. In addition, previous studies of high-dose therapy have not distinguished between those patients with progressive disease on primary induction therapy and those who have stable or only minimally responsive disease. These may represent distinct populations, since residual masses after initial chemotherapy, particularly in the mediastinum, may represent resolving fibrosis or necrosis rather than persistent active disease.^18,19

The present study was undertaken to determine the outcome for adult patients with Hodgkin's disease reported to the lymphoma registry of the European Group for Blood and Marrow Transplantation. These patients received high-dose therapy and ASCT after they were unable to enter remission after induction chemotherapy. In addition, univariate and multivariate analyses were undertaken to determine factors predictive of overall survival (OS) and progression-free survival (PFS).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Between November 1979 and October 1995, 281 adult patients receiving high-dose therapy and ASCT for Hodgkin's disease after failure of induction therapy were reported to the European Group for Bone Marrow Transplantation, from 69 centers in Europe. Induction failure was defined as failure to achieve a partial remission (PR), complete remission (CR), or complete remission (uncertain) (CR_u) after initial treatment with combination chemotherapy, using one or more regimens. The definition therefore included patients with disease progression and those with stable disease according to the Cotswolds criteria,²⁰ after at least one regimen. The records of all of these patients were reviewed and the reporting centers were contacted to provide additional information, particularly with respect to the nature of first- and second-line chemotherapy and the response to first- and second-line induction treatment.

Of the initial 281 patients, 175 were identified for whom complete information on induction therapy and response was available. The patients constitute the study population. The median age of this group was 26 years 6 months (range, 16 years 1 month to 54 years 9 months) at the time of diagnosis and 27 years 6 months (range, 17 years 1 month to 55 years 6 months) at the time of ASCT. The median time from diagnosis to transplantation was 1 year 1 month (range, 1 month to 12 years 9 months). Other characteristics of this patient group are shown in Table 1, and details of their first- and second-line chemotherapy regimens are shown in Table 2. Most patients received either mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or a related regimen, or MOPP alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or a variant alternating regimen, as first-line therapy. Twenty-nine patients received consolidative involved-field radiotherapy to sites of bulky disease, most commonly to the mediastinum. This was given as a component of first-line therapy in 20 patients and second-line therapy in nine patients.

Patients were assessed for response at varying times during induction therapy, according to the active protocols of the various institutions. Patients with obvious disease progression were transferred to an alternative treatment regimen as soon as disease progression was identified. In some centers, patients were reassessed after two or three cycles of induction therapy, and those not in CR, CR_u, or PR at this point were treated with an alternative regimen. In other centers, patients were formally reassessed 1 month after completion of chemotherapy, with or without consolidative radiotherapy, and identified as having achieved less than a partial response at this point. Response assessment involved repeat physical examinations and repeat of all investigations that previously had abnormal results. Radiologic assessment included plain x-ray and computed tomography scanning. Magnetic resonance imaging, gallium scintigraphy, and positron emission tomography scanning were not routinely used at most centers during the period of this study.

The median number of cycles of first-line therapy was six (range, one to 12). Seventy-four patients (42%) received six cycles of first-line therapy, and 27 (15%) received eight cycles. Fifty-three patients (29%) received less than six cycles of first-line therapy, and nine patients (5%) received more than eight. The response to first-line therapy was classified as disease progression in 88 patients (50%), and stable disease or minimal response in 87 (50%).

Of the 175 patients, 75 received high-dose therapy and ASCT after failure of one induction regimen, with no further attempt at remission induction with conventional-dose therapy. The remaining 100 patients received further conventional-dose remission induction therapy with a variety of different regimens, as shown in Table 2. The median number of cycles of second-line therapy was three (range, one to nine), with 54 patients receiving three cycles or less. As with first-line therapy, the timing of response assessment to second-line therapy was variable. However, patients were included in this analysis only if they had failed to achieve a CR, CR_u, or PR to second-line therapy where this had been given. Of the 100 patients who received second-line therapy before high-dose therapy, 34 had definite evidence of disease progression and 66 had stable or minimally responsive disease.

At the time of high-dose therapy, 97 patients (56%) had persistent mediastinal masses. One hundred thirty-nine patients had bulky disease, measuring more than 5 cm before the commencement of high-dose therapy.

High-Dose Therapy and Transplantation Procedures
The high-dose regimens varied according to the participating centers and their active protocols. Details of high-dose regimens are shown in Table 3. Ninety-two percent of patients received chemotherapy-only high-dose regimens, most commonly carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide, carmustine, and etoposide. Bone marrow was the only source of autologous stem cells in 136 patients (79%), peripheral-blood progenitor cells were the only source in 32 patients (18%), and five patients (3%) received both. Bone marrow purging, with mafosfamide, was used in six patients. All patients underwent high-dose therapy and ASCT in registered transplant centers.

Supportive measures, including antimicrobial and blood-product therapy, were given according to the protocols of the individual centers. Thirty-seven patients received hemopoietic growth factors after stem-cell reinfusion, most commonly granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor.

Statistical Analysis
Survival analyses were performed according to the method of Kaplan and Meier.²⁵ Overall survival was calculated from the date of autologous stem-cell reinfusion to the date of death from any cause. PFS was calculated from the date of ASCT to the date of death or the date of documented disease progression. Treatment-related deaths occurring within 90 days of the date of stem-cell reinfusion were defined as early and those occurring later were defined as late treatment-related deaths.

Univariate analysis was performed using the log-rank test, to identify patient characteristics that were predictive of outcome after ASCT. The factors examined in univariate analysis were as follows: sex, Ann Arbor stage at diagnosis (stage I/II v stage III/IV), age (< 40 years v 40 years), disease bulk at diagnosis (< 5 cm v 5 to 10 cm v > 10 cm), disease bulk at ASCT (< 5 cm v 5 to 10 cm v > 10 cm), high-dose regimen (chemotherapy only v chemotherapy +total-body irradiation), source of stem cells (bone marrow v peripheral-blood progenitor cells or both), number of induction regimens (one v two, ie, second-line chemotherapy or not), response to last induction chemotherapy regimen before high-dose therapy and ASCT, and time interval between diagnosis and high-dose therapy (< 550 days v 550 days). Multivariate analysis was performed using Cox's proportional hazards model. The factors examined were the same as those included in the univariate analysis.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Response and Survival
Responses to high-dose therapy and ASCT are summarized in Table 4, and the actuarial OS and PFS rates for the entire group are shown in Fig 1. With a median follow-up of 73 months, the 5-year actuarial OS for all patients is 36% and the PFS is 32%.

View larger version (11K): [in this window] [in a new window]   Fig 1. PFS and OS for entire group.

Prognostic Factors
The results of univariate and multivariate analyses are summarized in Table 5. Univariate analysis identified two factors predictive of PFS and OS. Patients who had received only one prior regimen had a superior PFS and OS compared with those who had also received second-line chemotherapy before ASCT (Fig 2). In addition, patients who received ASCT within 550 days (ie, 18 months) after diagnosis had a superior OS and a nonsignificant trend for superior PFS compared with those who received ASCT later than 550 days after diagnosis (Fig 3). In multivariate analysis, the predictive value of the extent of therapy before ASCT was lost. The interval between diagnosis and ASCT retained predictive value for OS but not for PFS. In those patients who received ASCT at less than 550 days after diagnosis, the difference in OS and PFS according to the extent of prior therapy was maintained, as shown in Fig 4. In contrast, in those patients who underwent ASCT at more than 550 days after diagnosis, this factor lost its predictive value, although the patient numbers are relatively small.

View larger version (24K): [in this window] [in a new window]   Fig 2. PFS (A) and OS (B) according to the use of second-line chemotherapy before ASCT.

View larger version (22K): [in this window] [in a new window]   Fig 3. PFS (A) and OS (B) according to the interval between diagnosis and ASCT.

View larger version (46K): [in this window] [in a new window]   Fig 4. PFS and OS according to use of second-line chemotherapy in patients with < 550 days from diagnosis to ASCT (A and B, respectively) and 550 days from diagnosis to ASCT (C and D, respectively).

The response to the chemotherapy regimen given immediately before high-dose therapy and ASCT had no apparent effect on outcome (Fig 5). PFS and OS were not significantly different between those patients with disease progression and those who had stable or minimally responsive disease.

View larger version (47K): [in this window] [in a new window]   Fig 5. PFS and OS according to response to chemotherapy regimen given before high-dose therapy in patients receiving only first-line therapy (A and B, respectively) and those receiving second-line therapy (C and D, respectively).

Toxicity
There were 24 early transplant-related deaths (within 90 days of ASCT). The causes included interstitial pneumonitis (eight patients) and bacterial or fungal infection (six patients). A further nine deaths were classified as late toxic deaths, giving a rate of 10% at 5 years by Kaplan-Meier analysis. Causes of late toxic deaths included bacterial or fungal infection (five patients), cardiac toxicity (two patients), and second malignancy (four patients).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The outlook for patients with Hodgkin's disease who do not enter a remission after first-line combination chemotherapy is poor. A study from the Milan Cancer Institute has reported the use of conventional-dose salvage therapy, including the lomustine, etoposide, and prednimustine regimen, in patients who do not enter remission after treatment with alternating MOPP/ABVD.⁶ The complete remission rate for the 29 patients was 41%. The 5-year actuarial OS for this group was only 12%, and none of the surviving patients was free of disease. Similar results have been reported by the National Cancer Institute, where the median survival time for 51 patients with induction failures on MOPP chemotherapy was only 16 months.⁵ A recent study from Stanford University has reported a more favorable outcome, with a 4-year actuarial OS of 38% for patients with primary refractory disease, although with longer follow-up, further relapses were observed.¹²

The results of several single-institution studies have suggested a superior outcome for patients who receive high-dose therapy and ASCT in this setting. A study from City of Hope National Medical Center recorded a 2-year disease-free survival rate of 67% for patients with induction failure, although this included only six patients with a median follow-up of only 25 months.⁷ Other centers have reported lower disease-free survival rates after high-dose therapy, although these have been higher than those reported for conventional-dose salvage therapy.

Chopra et al⁹ have reported on 46 patients with primary refractory Hodgkin's disease who were treated with carmustine, etoposide, cytarabine, and melphalan chemotherapy and autologous bone marrow transplantation. The 5-year actuarial PFS for this group was 33%. An identical 5-year disease-free survival rate was reported in 19 patients receiving high-dose chemotherapy and hyperfractionated total-body irradiation at Memorial Sloan-Kettering Cancer Center.⁸ In a small study of the use of a high-dose sequential regimen for relapsed or refractory Hodgkin's disease, Gianni et al¹⁰ reported a 14% 3-year actuarial PFS and 29% OS for patients with primary refractory disease. In the report from Stanford, the use of high-dose therapy for patients with induction failures produced a 4-year actuarial OS of 44%, and a 4-year freedom from progression of 52%.^12,13 These results were significantly superior to those of a matched patient group who received conventional-dose salvage therapy. Several other recent series have reported similar results.^14-17

The 5-year actuarial OS and PFS rates of 36% and 32%, respectively, in the present study are therefore very similar to those reported from single-institution series and to those reported from the Autologous Blood and Marrow Transplant Registry (ABMTR).²⁶ The ABMTR series comprises 122 patients with Hodgkin's disease who have never achieved remission. The definition of failure to achieve remission differs from that in our series in that it includes only those patients with documented disease progression or tissue confirmation of persistent disease in residual radiographic abnormalities. With a median follow-up of 28 months from the date of ASCT, the 3-year actuarial PFS and OS rates in this series are 38% and 50%, respectively.

Previous series have identified numerous prognostic factors with predictive value in this setting.^7-17 At the time of ASCT, disease bulk, performance status, bone marrow involvement, presence of B symptoms, elevated serum lactate dehydrogenase levels, extranodal disease, state, bone marrow involvement, and relapse within a previously irradiated field have all been shown to have predictive value for PFS, event-free survival, and/or OS. In view of the registry-based nature of the present study, data for many of these parameters were not available.

In common with several previous series, the extent of therapy before ASCT was a significant factor in univariate analysis. Patients who had received only one prior regimen had a significantly superior outcome to those who had received more than one. This is likely due to the fact that patients for whom two regimens fail represent a particularly poor prognostic group. Patients who responded to second-line therapy would have been excluded from this series and almost certainly represent a more favorable group. These results do not imply that patients should proceed directly to high-dose therapy after one prior regimen fails. Univariate analysis also identified the interval from diagnosis to ASCT as a significant prognostic variable. OS was superior in patients who underwent ASCT within 18 months (550 days) of diagnosis compared with those who underwent ASCT later. This result is partly due to the higher proportion of patients who received only one prior chemotherapy regimen in the "early" compared with the "late" transplant group (53% compared with 20%, respectively). This explanation is supported by the observation that the predictive value of extent of prior therapy is lost in multivariate analysis, whereas that for the time from diagnosis to transplant is maintained, at least for OS.

The assessment of response in Hodgkin's disease can be problematic, especially in the mediastinum, where residual masses are common after chemotherapy. These residual masses may contain active disease, but they may represent fibrotic masses with no residual disease.^18,19 Previous studies have demonstrated that the presence of a mediastinal mass after chemotherapy is associated with a higher relapse rate compared with no residual mass. However, about 60% to 70% of patients with residual mediastinal masses remain progression-free. Therefore, although patients with mediastinal disease may be classified as not having responded to induction therapy on the basis of routine radiologic assessment after chemotherapy, and may receive second-line therapy on this basis, it is possible that a proportion might remain progression-free with no further therapy.

Since a high proportion (56%) of the patients in this series had mediastinal involvement at the time of high-dosetherapy, and only routine radiologic assessment (plain x-ray and CT scanning) was available at most centers, it is possible that some patients underwent ASCT with residual masses that did not contain active disease. However, this is also likely to be true of most other published series of patients receiving ASCT in this context. Furthermore, the response to the regimen given immediately before transplantation was not predictive of outcome in our series. This suggests that the use of high-dose therapy and ASCT should be considered for patients with stable or minimally responsive disease as well as those with obvious disease progression.

The use of newer imaging techniques, such as gallium scintigraphy,^27,28 magnetic resonance imaging,²⁹ and positron emission tomography scanning,³⁰ has been shown to improve the discrimination between masses that contain active disease and residual fibrotic change. These techniques might allow identification of subgroups of nonresponding patients who may benefit from high-dose strategies in future studies.

The early toxic death rate of 14% in this series is comparable to that in other reports of patients with primary refractory disease. The corresponding early death rate in the recent Stanford series was 21%.¹²

In view of the retrospective, registry-based nature of this study, the results must be interpreted cautiously, particularly in view of the potential for selection bias for patients receiving high-dose therapy. However, the results from this study suggest that high-dose therapy and ASCT may be an effective strategy for patients with Hodgkin's disease who do not respond to induction chemotherapy, whether they have progressive disease or disease that is stable or only minimally responsive. This approach may be superior to conventional-dose salvage therapy. Confirmation of this observation requires a randomized prospective trial, with precisely defined criteria for the assessment of residual clinical and radiologic abnormalities.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following members of the European Group for Bone Marrow Transplantation contributed patients to this study: A. Fischer, Hopital Necker, Paris, France; A. Gratwohl, Kantonsspital, Basel, Switzerland; L. Jost, Universitatshospital, Zurich, Switzerland; N. Gorin, Hopital St Antoine, Paris, France; C. Rozman, Postgraduate School of Hematology, Barcelona, Spain; H.G. Prentice, Royal Free Hospital, London, United Kingdom; A.M. Carella, Ospedale S Martino, Genova, Italy; D. Cunningham, Royal Marsden Hospital, London, United Kingdom; A. Porcellini, Centro Trapianto Midollo Osseo, Cremona, Italy; H. Greinix, University of Vienna, Vienna, Austria; A. Parker, Royal Infirmary of Edinburgh, United Kingdom; M. Agglietta, Clinica Medica Universita, Turin, Italy; F. Mandelli, Universita "La Sapienza," Rome, Italy; J. Cahn, Hôpital Besancon, Besancon, France; A. Ferrant, Cliniques Universitaires St Luc, Brussels, Belgium; S. Tura, Hospital san Orsola, Bologna, Italy; T. Philip, CRLC Centre Leon Berard, Lyon, France; A. Ioiondo, Hospital Nacional "Marques de Valdecilla," Santader, Spain; I. Franklin, Glasgow Royal Infirmary, Glasgow, United Kingdom; V. Rizzoli, Centro Trapianto Midollo Osseo, Parma, Italy; G. Toriontano, Ospedale Civile, Pescara, Italy; F. Freycon, Hopital Nord, St Etienne, France; J. Verrant, Hopital Henri Mondor, Creteil, France; J. Harrousseau, Hotel Dieu, Nantes, France; B. McVerry, St James University Hospital, Leeds, United Kingdom; N. Schmitz, Christian Albrechts University, Kiel, Germany; A. Nagler, Hadassah University Hospital, Jerusalem, Israel; S. Brunet, Hospital Santa Creu I Sant Paul, Barcelona, Spain; V. Leblond, Pitie-Saltpetriere, Paris, France; L. Guilhot, Hopital la Militerie, Poitiers, France; A. Della Volpe, Universita di Milano, Milan, Italy; F. Jones, Royal Victoria Hospital, Belfast, United Kingdom; A. Newland, Royal London Hospital, London, United Kingdom; D. Hollard, Hopital A. Michallon, Grenoble, France; D. Niederweiser, University Hospital, Innsbruck, Austria; P. Colombat, Hopital Brettoneau, Tours, France; M. Iegros, Centre Jean Perrin, Clermont-Ferrard, France; S. Proctor, Royal Victoria Hospital, Newcastle, United Kingdom; D. Milligan, Heartlands Hospital, Birmingham, United Kingdom; E. Allesandrino, Centro Trapianto Midollo Osseo, Pavia, Italy; A. de Laurenzi, Ospedale san Camillo, Rome, Italy; K. Oezerkan, University Hospital, Ankara, Turkey; R. Carioli, Ospedale Niguarda, Milan, Italy; P. Coser, Hospital San Maurizo, Bolzano, Italy; M. Abecasis, Inst. Portugues Oncologia, Lisbon, Portugal; E. Nemet, University Hospital Centre-Rebro, Zagreb, Croatia; G. Leone, Universita Cattolica S Curore, Rome, Italy; K. Downs, St Vincents Hospital, Sydney, Australia; R. Clark, Royal Liverpool Hospital, Liverpool, United Kingdom; D. Winfield, Royal Hallamshire Hospital, Sheffield, United Kingdom; D. Samson, Charing Cross Hospital, London, United Kingdom; M. Greco, Ospedale Gen Reg della Fondazione, Rotondo, Italy; A. Fassas, The George Papanicolao Hospital, Thessaloniki, Greece; R. Marcus, Addenbrooke's Hospital, Cambridge, United Kingdom; H. Hansen, Herlev Hospital, Herlev, Denmark; N. Harhalakis, Evangelismos Hospital, Athens, Greece; M. Attal, Hôpital de Purpan, Toulouse, France; P. Lacor, University Hospital, Brussels, Belgium; V. Castel, Hospital Le Fe, Valencia, Spain; P. Lemoine, Hôpital Sud, Rennes, France; J.L. Pico, Institut Gustave Roussy, Villejuif, France; D. Caillot, Hôpital d'Enfants, Dijon, France; J. Sweetenham, University of Southampton, Southampton, United Kingdom; V. Koza, Faculty Hospital Alej-Svobody, Pils, Czech Republic; D. Caballero, Hospital Clinico, Salamance, Spain; U. Tidefeldt, Orebro Medical Center Hospital, Orebro, Sweden; T. Morris, Belfast City Hospital, Belfast, United Kingdom; and A. Hellman, Medical University of Gdansk, Gdansk, Poland.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted July 25, 1997; accepted May 28, 1999.

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