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Autotransplants for Hodgkin's Disease in Patients Never Achieving Remission: A Report From the Autologous Blood and Marrow Transplant Registry

Address reprint requests to Hillard M. Lazarus, MD, Department of Medicine, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106; email hml{at}po.cwru.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (ie, those with primary induction failure) have a poor prognosis. Some subjects who receive high-dose therapy with autologous hematopoietic progenitor-cell infusion experience prolonged progression-free survival.

PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 122 Hodgkin's disease patients who failed to achieve complete remission after one or more conventional therapy regimens and subsequently received an autotransplant between 1989 and 1995 were reviewed.

RESULTS: Median age was 27 years (range, 7 to 57 years). Median time from diagnosis to transplantation was 14 months (range, 5 to 38 months). Most patients received high-dose chemotherapy without radiation for pretransplantation conditioning (n = 107). The regimen most frequently used was cyclophosphamide, carmustine, and etoposide (n = 47). Fifteen patients received total-body irradiation (n = 15). The graft consisted ofbone marrow (n = 86), blood stem cells (n = 25), or both (n = 11). The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Sixty patients (50%) were considered to have achieved complete remission after autotransplantation; 37 of these had negative imaging studies, whereas scan abnormalities of unknown significance persisted in 23 patients. Twenty-seven patients (22%) had no response or progressive disease after transplantation. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, "B" symptoms at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome.

CONCLUSION: Autotransplants should be considered for patients with Hodgkin's disease who do not achieve complete remission with conventional therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
C<-pick;f1;0;0>HEMOTHERAPY ALONE OR with radiation cures 60% to 70% of patients with advanced Hodgkin's disease.^1-5 However, very few patients who fail to achieve remission with their first chemotherapy regimen (primary induction failure) survive 5 years.^6-17 There are few reports of autotransplantation in the setting of primary induction failure. We analyzed results of autotransplantations reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) in 122 people with Hodgkin's disease who had never achieved remission. Our objectives were to determine overall survival and progression-free survival and to identify patient-, disease-, and treatment-related variables correlated with outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ABMTR
The ABMTR is a voluntary organization of more than 170 transplantation centers primarily located in the United States, Canada, and Central and South America that report data on consecutive autotransplantations to a statistical center at the Medical College of Wisconsin. The ABMTR defines autotransplantation as treatment with a sufficiently high dose of chemotherapy to require autologous bone marrow or blood-derived hematopoietic stem cell support. The ABMTR began data collection in 1992. Data were collected retrospectively for patients who received autotransplants between 1989 and 1992 and prospectively thereafter. Participating centers register basic information on consecutive autotransplants for all disease indications. Comprehensive clinical data are collected for a sample of these patients. According to data collected in the Centers for Disease Control Hospital Surveys,^18,19 approximately one half of autotransplantations performed in North America were registered with the ABMTR during the study period. Participating centers are listed in the Appendix. Physician review of submitted data, computerized error checks, and on-site audits ensure data accuracy. Patients are followed longitudinally, and information on progression and death is requested yearly.

Patients
Between January 1, 1989, and December 30, 1995, a total of 3,063 autotransplants for Hodgkin's disease were registered with the ABMTR. Of these, 332 transplantations were performed in people who had never achieved complete remission. Comprehensive data were available for 122 (39%) of these subjects. Age, sex, type of graft, and outcome were similar in patients with and without comprehensive data.

Subsequent analyses were restricted to the 122 patients with comprehensive data whose transplants were received between 1989 and 1995. Patients were reported to the ABMTR by 37 centers. Median follow-up was 28 months after autotransplantation. Patients were considered to have primary induction failure if they had never achieved complete remission after completing at least one regimen of combination chemotherapy. Because Hodgkin's disease patients successfully treated with chemotherapy may have residual radiographic abnormalities, patients with persistent scan abnormalities without progression in other sites or tissue confirmation of persisting disease were not considered to be induction failures.²⁰

Statistical Methods
Probabilities of 100-day mortality (death from any cause in the first 100 days after transplantation), progression-free survival, and overall survival were calculated using the Kaplan-Meier product-limit estimate.²¹ Progression was defined as any increase in size of existing sites of disease, development of new sites of disease, or recurrence of disease in patients achieving a complete remission posttransplantation. All patients had follow-up through 100 days posttransplantation. For calculations of overall survival and progression-free survival, patients were censored at the time of last follow-up.

Cox proportional hazards regression was used to examine the association between survival and patient-, disease-, and treatment-related variables.²² Variables examined included age, gender, histology, presence of mediastinal mass at diagnosis, presence of "B" symptoms (weight loss of > 10% body weight in 6 months, unexplained fever of > 38°C, or night sweats) at diagnosis, tumor chemosensitivity (partial v no response v unknown), disease stage at diagnosis, Karnofsky performance score pretransplantation, type of hematopoietic graft, high-dose preparative regimen, hematopoietic growth factor use, year of transplantation, disease stage at transplantation, liver or bone marrow involvement, splenectomy, and time from diagnosis to transplantation. Chemosensitivity information was not available for about one third of patients because it was not captured by early versions of the ABMTR report forms. Partial response was defined as a 50% or greater reduction in greatest dimension of all sites of known disease and no new sites of disease for at least 4 weeks. The assumption of proportional hazards over time was tested for all explanatory covariates, using a time-dependent covariate. The tests indicated that all covariates had constant relative risks over time.

A forward stepwise model-building technique was used. Within each model, one additional significant covariate factor was added at each step, and the remaining covariates were re-examined. When there were no further covariate factors significant at P = .05, model building was stopped. First-order interactions of significant covariates were tested.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient-related variables are listed in Table 1. The median age of the patients was 27 years (range, 7 to 57 years), and 60% were male. At diagnosis, 71% had nodular sclerosis histology, 65% had stage III or IV disease, and 57% had B symptoms; approximately three quarters had a mediastinal mass. Eleven percent had evidence of extranodal involvement (ie, liver or bone marrow) at some time pretransplantation. All patients received chemotherapy, usually with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or a similar regimen (17%); doxorubicin, bleomycin, vinblastine, and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (ABVD) (34%); or an alternating or hybrid MOPP-ABV(D) regimen (34%).^2,5 Fifty-eight percent of patients received a second induction regimen, and 40% received radiation therapy.

Forty-three percent of patients had pretransplantation Karnofsky performance scores of less than 90%. More than half had stage III or IV disease pretransplantation. Among the 80 patients in whom sensitivity to conventional-dose chemotherapy was known, 56% responded to pretransplantation chemotherapy despite failure to achieve complete remission, whereas 44% had less than a partial response. Eighty percent of patients received a bone marrow autograft with or without blood stem cells. Twelve percent of the grafts were manipulated in vitro to remove tumor cells. The most commonly used transplant preparative regimen was cyclophosphamide, carmustine, and etoposide. Thirty-nine percent of patients underwent autotransplantation within 1 year of diagnosis. Seventy-five patients (62%) received recombinant hematopoietic growth factors after transplantation to facilitate hematopoietic recovery.

Sixty patients (50%) achieved a complete remission after transplantation (Table 2). In 37 patients (31%), posttransplantation scans were negative, whereas abnormalities of uncertain significance persisted in 23 patients (19%). Sixteen percent of patients had a partial response, and one quarter had less than a partial response to high-dose therapy. The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Three-year probabilities of survival and progression-free survival were 50% (95% confidence interval, 39% to 60%) and 38% (95% confidence interval, 28% to 48%), respectively (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. Probability of overall survival and progression-free survival (PFS) after autotransplantation for Hodgkin's disease in patients never achieving remission.

In multivariate analysis, only two variables in Table 1 significantly correlated with survival: B symptoms at diagnosis and Karnofsky performance score at autotransplantation (Fig 2). B symptoms were associated with a nearly 2-fold increased mortality risk, and a Karnofsky performance score of less than 90% was associated with a nearly two-fold risk (Fig 3). The 2-year probability of survival for patients without B symptoms at diagnosis and with pretransplantation Karnofsky scores of 90% to 100% was 87% (95% confidence interval, 63% to 96%); for those with B symptoms and with lower Karnofsky scores, it was 38% (95% confidence interval, 20% to 55%). Patients with only a single adverse prognostic factor had 2-year probabilities of survival of 56% (95% confidence interval, 33% to 74%) (Karnofsky score < 90% but no B symptoms) and 55% (95% confidence interval, 35% to 72%) (B symptoms with Karnofsky scores 90%). Chemosensitivity was not significantly associated with survival in the multivariate analysis. The 2-year probability of survival was 56% (95% confidence interval, 37% to 75%) in 44 patients with chemosensitive disease, 44% (95% confidence interval, 27% to 63%) in 34 patients with resistant disease, and 49% (95% confidence interval, 30% to 67%) in 41 patients in whom chemosensitivity was unknown (P = not significant).

View larger version (18K): [in this window] [in a new window]   Fig 2. Probability of survival after autotransplantation for Hodgkin's disease in patients never achieving remission by presence of B symptoms and Karnofsky performance score (KPS).

View larger version (14K): [in this window] [in a new window]   Fig 3. Relative risk of death after autotransplantation for Hodgkin's disease in patients never achieving remission by presence of B symptoms and Karnofsky performance score.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Survival of patients with Hodgkin's disease who do not achieve complete remission with initial therapy is poor. Longo et al⁶ reported a median survival of 16 months in 51 subjects who never achieved complete remission; no patient was alive at 8 years. Bonadonna et al¹¹ reported less than 15% long-term disease-free survival. Hagemeister et al¹³ noted that only 11 of 47 patients given conventional rescue chemotherapy achieved complete remission; the median survival was 50 weeks. Brusamolino et al¹⁷ and Schulman et al¹⁴ reported similar data. In a recent report of 115 patients failing to achieve remission with alternating or hybrid MOPP-ABVD induction therapy, the 8-year survival was only 8%.¹⁶

In contrast, our data from 122 patients receiving high-dose therapy and autotransplantation as second- or third-line salvage therapy after primary induction failure shows a 50% overall survival and 38% progression-free survival 3 years after autotransplantation. There are few large series examining the use of autotransplants in patients failing initial induction therapy. Table 3 lists the results of published autotransplantation trials in Hodgkin's disease with at least 10 patients who never achieved complete remission. Although early death rates varied considerably, at least one third of the patients seemed to have long survival. Sweetenham et al³⁵ recently reported in preliminary fashion the results of 290 autotransplantations performed for primary induction failure from 1979 through 1995 at 62 European centers. Patient characteristics and transplant-related mortality (14%) were similar to those of the subjects in this report. Actuarial 5-year overall and disease-free survival rates were 34% and 30%, respectively.

There are no randomized trials comparing conventional salvage chemotherapy to autotransplantation in patients with Hodgkin's disease who have not achieved complete remission with initial therapy. A single-center study by Yuen et al²³ reported improved outcome after autotransplantation compared with a historical control group given conventional salvage chemotherapy for refractory Hodgkin's disease. Thirteen of 60 patients in this matched comparison underwent autotransplantation for primary induction failure; the 4-year event-free survival was 52% in those treated with an autograft, compared with 19% in the conventional treatment group.

Although the results of autotransplantation in this study appear to be superior to those with conventional chemotherapy, one cannot discount potential patient selection bias, which is inherent in transplantation studies. The long intervals (median, 14 months) between diagnosis and transplantation may select for patients with a better prognosis, because patients with more aggressive disease may die earlier. Another drawback of our analysis is that it is not possible to determine how many patients were excluded from transplantation because of continued disease progression. Also, some centers require sensitivity to conventional-dose salvage chemotherapy as a prerequisite for autotransplantation,³⁶ but such selection criteria were not applied to all patients in this study, although even patients with chemotherapy-resistant disease had a 2-year survival of more than 40%. Although a randomized trial would best answer this question, it is unlikely that such a study will be undertaken owing to the relatively small numbers of patients not achieving remission with current therapy and their known poor prognosis with conventional salvage approaches.

Of the many variables that we examined, only B symptoms at diagnosis and Karnofsky performance score at transplantation were correlated with survival. The absence of both of these indicators of poor prognosis was associated with an excellent 2-year survival of 87%. Two-year survival was 56% in patients with one adverse factor and only 38% in those with both factors. Table 4 lists variables identified as important in prior studies of autotransplantation for relapsed or refractory Hodgkin's disease. Several studies noted correlation of outcome with B symptoms and performance score, as seen in this study. Some also noted associations with bulky disease and mediastinal tumors. We did not observe such relationships, although most of the patients in this study had bulky disease. Nearly three quarters of them had a mediastinal mass at presentation. Strauss et al⁴⁷ and Desablens et al²⁴ reported that initial treatment failures in Hodgkin's disease were more frequent in patients with large mediastinal tumors at presentation. Surprisingly, sensitivity to chemotherapy was not a significant predictor of survival, although more than 80% of patients with chemotherapy-resistant disease had B symptoms and/or low performance scores.

Our data demonstrate that some patients failing primary induction therapy for Hodgkin's disease can attain long-term overall and progression-free survival with an autotransplant. These results support the early use of transplants rather than conventional second- and third-line regimens in this setting.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

	ACKNOWLEDGMENTS

 
Supported in part by Public Health Service grants no. P30CA43703, P01-CA40053, and U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute of the U.S. Department of Health and Human Services; and by grants from Alpha Therapeutic Corporation; Amgen, Inc.; Anonymous; Baxter Healthcare Corporation; Bayer Corporation; Berlex Laboratories; BioWhittaker, Inc.; Blue Cross and Blue Shield Association; Bristol-Myers Squibb Company; CellPro, Inc.; Cell Therapeutics, Inc.; Centeon; Center for Advanced Studies in Leukemia; Chimeric Therapies, Inc.; Chiron Therapeutics; COBE BCT, Inc.; Genentech, Inc.; Human Genome Sciences; ICN Pharmaceuticals; Immunex Corporation; The Kettering Family Foundation; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation; MGI Pharma, Inc.; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; NeXstar Pharmaceuticals, Inc.; Novartis Pharmaceuticals; Orphan Medical; Ortho Biotech, Inc.; Pfizer, Inc.; Pharmacia and Upjohn; Principal Mutual Life Insurance Company; Roche Laboratories; SangStat Medical Corporation; Schering Oncology; Searle; SmithKline Beecham Pharmaceuticals; SyStemix; and United Resource Networks

	NOTES

 
From the Lymphoma Working Committee of the Autologous Blood and Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI; Department of Medicine, Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Department of Medicine, M.D. Anderson Cancer Center, Houston, TX; Division of Bone Marrow and Stem Cell Transplantation, Salick Health Care, Inc., Los Angeles, CA; Toronto Hospital and Ontario Cancer Institute, Toronto, Ontario, Canada; Johns Hopkins Oncology Center, Baltimore, MD; Markey Cancer Center, University of Kentucky, Lexington, KY; and Section of Hematology/Oncology, University of Illinois, Chicago, IL.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted June 1, 1998; accepted October 20, 1998.

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