¹Department of Medicine, Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio, USA

²Lymphoma Working Committee of the Autologous Blood and Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

³Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA

⁴Bone Marrow Transplant Program, University of Massachusetts Medical Center, Worcester, Massachusetts, USA

⁵Division of Hematology/Oncology, University of California, San Diego, California, USA

⁶Bone Marrow Transplant Program, Cleveland Clinic Foundation, Cleveland, Ohio, USA

⁷Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

⁸Division of Hematology/Oncology, University of Texas Health Science Center, San Antonio, Texas, USA

⁹Center for Advanced Studies in Leukemia, Los Angeles, California, USA

¹⁰Haematology Department, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

¹¹James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA

¹²Texas Transplant Institute, San Antonio, Texas, USA

¹³Bone Marrow Transplant Unit, Bristol Royal Hospital for Sick Children, Bristol, UK

¹⁴Scripps Clinic and Research Foundation, La Jolla, California, USA

¹⁵Bone Marrow Transplant Program, Tulane University Medical Center, New Orleans, Louisiana, USA

¹⁶Bone Marrow Transplant Program, Fundaleu, Buenos Aires, Argentina

¹⁷Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA

¹⁸Section of Hematology/Oncology, University of Illinois, Chicago, Illinois, USA

Correspondence to: Dr H M Lazarus, Department of Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106 USA.

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

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse. Bone Marrow Transplantation (2001) 27, 387-396.

Hodgkin's disease; autotransplant; relapse; second complete remission

The treatment of Hodgkin's disease represents one of the 'success' stories of modern oncology. Five-year survival of newly diagnosed patients is >80% in a recent series.¹ More than 80% of patients with early stage Hodgkin's disease and more than half with advanced stage disease are cured with chemotherapy, radiation, or a combination.^{2,3,4,5,6,7,8,9,10,11,12,13,14,15,16} Once patients relapse after initial therapy, however, conventional-dose chemotherapy regimens usually fail to provide durable complete remissions.^{17,18,19,20,21,22,23,24} In the series with the longest follow-up, Longo and associates¹⁷ reported that although 93% of relapsing patients could be re-induced into a second complete remission, only 17% of these remissions were durable. Other studies confirm that only a minority of patients experience prolonged disease-free survival with salvage chemotherapy.^{19,20,22,23,24} Consequently, high-dose therapy with autologous hematopoietic stem cell support (autotransplantation) is increasingly used to treat recurrent Hodgkin's disease. We analyzed results of autotransplantations reported to the Autologous Blood and Marrow Transplant Registry (ABMTR), performed in 414 people with Hodgkin's disease in first relapse or second complete remission. Our objectives were to determine overall and disease-free survival and to identify patient-, disease-, and treatment-related variables correlated with outcome.

Methods

ABMTR

The ABMTR is a voluntary organization of more than 170 transplant centers in the United States, Canada, Central and South America and Australia 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. The ABMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, pretransplant remission status, date of diagnosis, graft type (bone marrow- and/or blood-derived stem cells), purging, high-dose conditioning regimen, post-transplant status and survival. Updates on disease and survival status for registered patients are requested at 6 month intervals. All ABMTR teams contribute registration data. Research data are collected on subsets of registered patients and include comprehensive pre- and post-transplant clinical information. 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 annually. Based on data collected by the Centers for Disease Control Hospital Surveys,^25,26 approximately one-half of autotransplantations in North America were registered with the ABMTR during the study period.

Patients

Between 1 January 1989 and 31 December 1995, 990 autotransplants for Hodgkin's disease in first relapse or second complete remission were registered with the ABMTR. Research data (see above) were available for 425 (43%). Survival and demographics of these patients were similar to those of all registered patients. Relapse is defined as recurrence of Hodgkin's disease after a documented complete remission lasting at least 1 month. Second complete remission is defined as complete disappearance of all known disease for at least 4 weeks, induced after a first relapse and before autotransplant. Partial remission is defined as having at least 50% reduction in greatest diameter of all sites of known disease and without any new sites. Eleven patients did not have sufficient data for key variables to be included in the multivariate analysis. To maintain homogeneity in the sample utilized for all multivariate models, these patients were excluded leaving comprehensive data available for 414 subjects. Patients were reported to the ABMTR by 84 centers in eight different countries. Median follow-up was 46 months (5-96 months) after autotransplantation.

Statistical methods

Outcomes studied were 100-day mortality, relapse, disease-free survival, and overall survival. Probabilities of 100-day mortality (death from any cause in the first 100 days after transplant), disease-free survival and overall survival were calculated using the Kaplan-Meier product limit estimate.²⁷ Relapse was evaluated in patients surviving 28 days post transplant. Patients were censored at last follow-up or death in continuous complete remission. Both persistent disease or recurrence were considered as relapse. Patients with persistent disease were considered to relapse at day 28. Surviving patients without persistent or recurrent disease were censored at last follow-up. Disease-free survival was defined as survival in complete remission; persistent or recurrent disease and non-relapse deaths were events.

Assessment of potential risk factors for outcomes of interest was performed using multivariate Cox proportional hazards regression.²⁸ Variables included in model building are shown in Table 1. All computations used the procedure PHREG in the statistical package SAS. Forward stepwise variable selection at a 0.05 significance level was used to identify covariates associated with outcomes. The assumption of proportional hazards was tested using a time-dependent covariate for all variables; when this indicated differential effects over time (non-proportional hazards), models were constructed breaking the post-transplant course into two time periods using the maximized partial likelihood method to find the most appropriate breakpoint. First order interactions were tested for all significant covariates. Overall covariate effects were tested using the Wald test. All multivariate models were examined for center effects using a random effects or frailty model;²⁹ there were no significant center effects.

Results

Characteristics of the study population are shown in Table 2. Median age was 29 years (range, 7-64 years) and 60% were male. At diagnosis, 71% had nodular sclerosis histology, 60% had stage III or IV disease, approximately one-quarter had a performance score <90%, and 60% had 'B' symptoms. Eleven percent had bone marrow involvement at diagnosis. Ninety-five percent of patients initially received chemotherapy, with or without radiation therapy, usually MOPP or a similar regimen (13%), ABVD (27%), or an alternating or hybrid MOPP-ABV(D) regimen (47%). Sixty percent of patients achieved their first complete remission with one chemotherapy regimen, radiation alone, or a combination.

The median time from diagnosis to relapse was 18 months (range, 6-219 months); nearly 80% of patients relapsed more than 1 year after diagnosis. Thirteen percent of patients had a tumor mass 5 cm or larger at relapse. Ninety-four percent of patients received salvage chemotherapy prior to autotransplant. Nearly half received two or more cycles of such therapy. Eighty-three percent of patients had chemotherapy-sensitive disease, defined as achievement of >50% reduction in all sites of disease, with no new sites of disease. Thirty percent (n = 119) achieved second complete remission and about half (n = 207) had a partial remission prior to transplantation. Only 11% (n = 41) of patients had chemotherapy-resistant relapse. One quarter of patients had Karnofsky performance scores <90% and one-quarter had elevated serum lactic dehydrogenase (LDH) levels at transplant. The most commonly used high-dose preparative regimen was CBV (cyclophosphamide, BCNU (carmustine), VP-16 (etoposide)). Total body irradiation was used in only about 10% of patients and another 20% received radiotherapy to involved-fields either immediately before or after the transplant. Forty-one percent of patients received peripheral blood hematopoietic stem cell grafts with or without bone marrow cells.

Of the 295 patients not in remission at transplant, 165 (56%) achieved complete remission post transplant. Sixty-one (37%) of these subsequently recurred. Twenty-four (20%) patients transplanted in complete remission recurred.

With a median follow up of 46 (range, 5-96) months, the 3-year probability of survival (95% confidence interval) for all patients was 63 (58-68)%. Probability of survival at 3 years was 58 (52-64)% for patients transplanted in first relapse compared to 75 (66-83)% for patients in second remission (P < 0.001) (Figure 1). Among patients in relapse, 3-year survival was 65 (57-71)% for patients with chemotherapy-sensitive disease, 37 (22-52)% for those with resistant relapse and 51 (35-65)% for those with untreated relapse or unknown sensitivity (Figure 1). Similarly, the probability of disease-free survival at 3 years was 46 (40-52)% for patients transplanted in first relapse vs 64 (53-72)% for those in second remission (P < 0.001). Among patients in relapse, 3-year disease-free survival was 53 (45-60)% for patients with chemotherapy-sensitive disease, 19 (8-33)% for those with resistant relapse and 19 (8-33)% for those with untreated relapse or unknown sensitivity.

One hundred and twenty-two of 414 (29%) patients died (Table 3). The main cause of death was Hodgkin's disease. Twenty-nine (7% of all patients transplanted) died within 100 days of transplant. Seventeen of these (4% of all patients transplanted) died of causes related to toxicity of the transplantation procedure, ie non-relapse deaths. Ninety-three patients died more than 100 days after transplant. Twenty-one of these (5% of all patients transplanted) died of late non-relapse complications such as interstitial pneumonitis, infection, or organ failure.

In the multivariate analysis of treatment failure (eg relapse or death) only four variables in Table 1 had statistically significant correlations: disease sensitivity to chemotherapy, serum LDH at transplant, Karnofsky performance score at transplant and initial chemotherapy used (Tables 4, 5> and 6). Compared to patients in second complete remission, patients not in remission generally had a higher risk of treatment failure; resistance to salvage treatment conferred nearly a 3½-fold increase in risk (Table 4). Abnormal serum LDH was associated with a two-fold increase and Karnofsky performance status <90% was associated with a nearly 1½-fold increased risk of treatment failure (Table 4). Similarly, the risk of relapse correlated with pretransplant disease state and serum LDH (Table 5). Finally, the risk of death correlated with type of chemotherapy given for initial therapy in addition to chemotherapy-sensitivity, LDH and performance status (Table 6, Figures 1, 2, 3 and 4). Patients relapsing after receiving MOPP at diagnosis had worse outcome than those receiving other regimens (Table 6, Figure 4).

Discussion

The results of this study suggest that high-dose cytotoxic therapy and autologous hematopoietic stem cell transplantation may produce long-term disease-free survival in patients relapsing after initial chemotherapy for Hodgkin's disease. Although the results appear better than those reported for conventional salvage regimens, the findings must be interpreted cautiously in view of the observational nature of the study and the potential for patient selection bias. Unfortunately, there is only a single, small, prospective randomized trial published that addresses the question of whether autotransplantation is superior to non-transplant therapy in patients with relapsed or refractory Hodgkin's disease. That study, by Linch and co-workers,³⁰ found superior event-free survival after autotransplantation compared to a salvage regimen that is not widely used, ie one with the same agents utilized in the pre-transplant conditioning regimen, but in non-myeloablative doses. There was no difference in overall survival, probably because some patients failing 'conventional' therapy were successfully salvaged by autotransplantation. The Linch study was not designed to look specifically at patients in first relapse or second complete remission, but also included patients failing initial therapy and those in second relapse.

Brice and colleagues³¹ performed a retrospective analysis of 187 patients with Hodgkin's disease in first relapse treated with conventional therapy or autotransplantation. Although there were no significant differences in overall survival or freedom from second failure, the transplant group had more adverse factors at relapse. A trend for better outcome was seen with autotransplantation in patients with more widespread disease at relapse and/or with an initial remission duration of <12 months.

The survival and disease-free survival rates reported in the current study are similar to those in most other single institution and registry studies (Table 7). Reported disease-free and overall survival rates are as high as 61-79%.^{32,33,34,35,36,37,38,39} Although all of the series in Table 7 examined the outcome of autotransplantation in first relapse, eligibility criteria differed. For example, the studies by Yahalom et al,³² Chopra et al,³³ and Nademanee et al³⁵ included only patients relapsing within 1 year of completing therapy and/or failing to respond to salvage chemotherapy. The series by Reece et al³⁹ specifically excluded patients anticipated to have a good prognosis with conventional chemotherapy. Nonetheless, disease-free survival rates generally exceeded 40-45% even in patients with unfavorable characteristics.

Early non-relapse mortality was low in the current series, as in other series in which the data are available. Early toxic death rates are generally less than 5% in this setting, lower than seen in patients transplanted with more advanced or resistant disease.^{32,33,41,42,43,44} As shown in Table 7, investigators often report treatment-related mortality for all patients in their series, which hampers practitioners in ascertaining the risk for patients with specific characteristics. However, the low risk of fatal toxicity and consistently favorable outcomes all support the use of transplantation as the preferred treatment of patients in first relapse or second remission.

In our study the outcome of patients in second complete remission was significantly better than that of patients in either chemotherapy-sensitive or resistant first relapse. The strategy for utilizing salvage chemotherapy in Hodgkin's disease reflects, in part, data generated in relapsed non-Hodgkin's lymphoma, where disease status at autotransplantation predicts outcome.⁴⁵ Such an analysis, however, is hampered by the fact that remission status can be difficult to determine when residual masses are present. Furthermore, achievement of complete remission before transplantation may simply reflect less aggressive tumor biology leading to increased likelihood of cure regardless of treatment. One cannot predict anti-tumor response to salvage therapy, and some patients in first relapse may never achieve second complete remission. Some of these subjects may not proceed to transplantation because of intercurrent medical problems associated with multiple attempts to induce remission. This inherent selection bias may explain, in part, the less favorable results in untested relapse patients, reported by groups such as Sweetenham and colleagues³⁴ and Arranz et al.⁴⁰ Thus, superior results for second complete remission patients may not be the result of a beneficial effect of re-induction therapy but rather from identification of good prognosis patients.

Of the many variables examined in multivariate analysis (Table 1), only Karnofsky performance score <90%, abnormal serum LDH, resistant relapse, and MOPP therapy at diagnosis were adverse prognostic factors for disease-free survival. Several investigators have identified poor prognostic factors in heterogeneous patient groups including individuals with more advanced relapse or those who failed initial induction therapy. Fewer studies have examined prognostic factors specifically in first relapse or second remission patients (Table 8). In keeping with our findings, Lumley and associates⁵⁰ reported elevated serum LDH at transplant to be unfavorable, while Jagannath et al,⁴⁶ Wheeler et al,³⁸ Reece et al,⁴³ Horning et al,⁴⁹ Bierman et al,⁵¹ and Anderson et al⁵² identified abnormal performance status as a predictor for poor outcome. We also corroborated the observations of several noting that resistant relapse heralded an inferior result after transplant.^38,42,47 It is unclear why MOPP therapy at diagnosis provided inferior outcome, and no single cause of death accounted for this finding.

Persistent or recurrent Hodgkin's disease was the major cause for failure; 69% of deaths resulted from progressive tumor. This suggests that strategies designed to address minimal residual disease should be explored to improve upon current results. One approach involves the complementary role of involved-field radiation therapy in conjunction with high-dose chemotherapy. The inclusion of such radiotherapy recently was shown to be of benefit when used in the peri-transplant setting in non-Hodgkin's lymphoma (JM Vose, unpublished observations). Data from three series^33,41,46 suggest a benefit for this modality in autotransplants for recurrent Hodgkin's disease. Patient selection clearly plays a role, as such treatment may be feasible in only a minority of patients due to prior radiation exposure, disease involving multiple sites, or low blood cell counts. We did not observe a benefit in this study but the number of patients receiving involved-field radiotherapy was relatively small.

Post-transplant immunotherapy for minimal residual disease is another intriguing approach. Immunotoxins directed against Reed-Sternberg cell antigens CD15, CD25, CD30, CD40, and CD80⁵⁴ have been employed in clinical trials with varying degrees of success.^55,56,57 Another novel approach includes the IL-2/diphtheria fusion toxin, which was associated with some success when given as a sole salvage modality.⁵⁸ Allogeneic transplantation may provide a potent graft-versus-lymphoma effect. However, despite lower relapse rates, the high treatment-related mortality currently associated with allogeneic transplantation make it unlikely to improve survival compared with autografts.⁵⁹ It is possible that allotransplantation done with non-myeloablative conditioning regimens may give a better result if early indications of lower regimen-related toxicity prove true. Another potentially promising approach is tandem transplantations. Ahmed et al⁶⁰ demonstrated that chemotherapy-refractory patients had an outcome similar to chemotherapy-sensitive patients if two courses of high-dose therapy, each with autotransplantation, were given. One recent approach is to perform autotransplantation followed by non-myeloablative allotransplantation, thus combining dose-intensive and immune-mediated anti-tumor approaches. These and other approaches to improving tumor eradication with acceptable toxicity should be the object of future investigations.

Acknowledgements

This study was supported, in part, by Public Health Service Grant No. P30-CA43703 from the National Cancer Institute and by Public Health Service Grants Nos 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 US Department of Health and Human Services; and by grants from Amgen, Inc.; Anonymous; Baxter Fenwal; Berlex Laboratories; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Oncology; Cell Therapeutics; Center for Advanced Studies in Leukemia; Chimeric Therapies; Chiron Therapeutics; COBE BCT Inc.; Eleanor Naylor Dana Charitable Trust; Deborah J Dearholt Memorial Fund; Empire Blue Cross Blue Shield; Eppley Foundation for Research; Fromstein Foundation; Fujisawa Healthcare, Inc.; Genentech, Inc.; Hoechst Marion Roussel; Horizon Medical Products; Human Genome Sciences; IDEC Pharmaceuticals; Immunex Corporation; IMPATH/BIS; IntraBiotics Pharmaceuticals; Kaiser Permanente; Kettering Family Foundation; Kirin Brewery Company; Robert J Kleberg, Jr and Helen C Kleberg Foundation; Herbert H Kohl Charities; LifeTrac/ Allianz; The Liposome Company; Nada and Herbert P Mahler Charities; Market Certitude; Mayer Ventures; MDS Nordian; MedImmune, Inc.; Milliman & Robertson, Inc.; Milstein Family Foundation; Miltenyi Biotech; Milwaukee Foundation/Elsa Schoeneich Research Fund; Mutual of Omaha; Nexell Therapeutics; NeXstar Pharmaceuticals, Inc; Samuel Roberts Noble Foundation; Novartis Pharmaceuticals; Orphan Medical; Ortho Biotech, Inc.; John Oster Family Foundation; Jane and Lloyd Pettit Foundation; Pfizer, Inc.; Pharmacia and Upjohn; Principal Life Insurance Company; Protide Pharmaceuticals; RGK Foundation; Rhône-Poulenc Rorer Pharmaceuticals, Inc.; Roche Laboratories; SangStat Medical Corporation; Schering AG; Schering-Plough Oncology; Searle; SmithKline Beecham Pharmaceutical; Stackner Family Foundation; The Starr Foundation; StemCell Technologies; SyStemix; Therakos; TheraTechnologies; United Resource Networks; US Oncology; and Wyeth-Ayerst Laboratories.

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Figure 1 Probability of survival after autotransplant for Hodgkin's disease in second complete remission or first relapse, according to sensitivity to salvage chemotherapy.

Figure 2 Probability of survival after autotransplant for Hodgkin's disease in second complete remission or first relapse, according to serum LDH at transplant.

Figure 3 Probability of survival after autotransplant for Hodgkin's disease in second complete remission or first relapse, according to Karnofsky performance score at transplant.

Figure 4 Probability of survival after autotransplant for Hodgkin's disease in second complete remission or first relapse, according to initial chemotherapy regimen administered.

Table 1  Variables tested in multivariate analysis

Table 2  Patient, disease, and transplant characteristics of patients receiving autotransplants for Hodgkin's disease in first relapse or second complete remission

Table 2  Continued

Table 3  Causes of death among patients receiving autotransplants for Hodgkin's disease in first relapse or second complete remission

Table 4  Multivariate analysis of treatment failure (relapse or death) among patients with Hodgkin's disease receiving autotransplants in first relapse or second complete remission^a

Table 5  Multivariate analysis of relapse among patients with Hodgkin's disease receiving autotransplants in first relapse or second complete remission^a

Table 6  Multivariate analysis of overall mortality among patients with Hodgkin's disease receiving autotransplants in first relapse or second complete remission^a

Table 7  Results of published series of autotransplants for Hodgkin's disease in first relapse or second complete remission

Table 8  Factors predicting poor outcome in prior studies of autotransplants for relapsed or refractory Hodgkin's disease