High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin's disease patients following first relapse after chemotherapy

Annals of Oncology 1: 151-156, 1996. O 1996 Kluwer Academic Publishers. Printed in the Netherlands.

Original article High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin's disease patients following first relapse after chemotherapy P. J. Bierman,1 J. R. Anderson,2 M. B. Freeman,1 J. M. Vose,1 A. Kessinger,1 M. R. Bishop1 & J. O. Armitage1 1

Department of Internal Medicine, Section of Oncology/Hematology and 2Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE, U.S.A.

patients treated initially with a four-drug regimen was not significantly different than patients treated with seven/eightBackground: The best results of conventional-dose salvage drug regimens. chemotherapy for Hodgkin's disease have been reported Conclusion: These results appear to be better than those after first relapse. We evaluated the results of high-dose reported for conventional-dose salvage chemotherapy. Highchemotherapy and autologous hematopoietic rescue for dose therapy followed by autologous bone marrow or peHodgkin's disease patients who had relapsed from an initial ripheral blood stem cell transplantation should be considchemotherapy-induced complete remission. ered for any patient with relapsed Hodgkin's disease, regardPatients and methods: Eighty-five patients received high- less of the length of initial remission, or type of initial dose cyclophosphamide, carmustine, and etoposide (CBV) chemotherapy. Certain patients, especially those with minifollowed by autologous bone marrow or peripheral blood mal disease, may benefit by proceeding directly to transplantation after relapse, without first receiving conventional-dose stem cell transplantation. Results: Actuarial survival at five years was 51%, and fail- salvage chemotherapy. ure-free survival was 40%. Failure-free survival at five years was 90% for patients who received no conventional-dose sal- Key words: bone marrow transplantation, drug therapy, vage chemotherapy prior to CBV. Failure-free survival of hematopoietic stem cell transplantation, Hodgkin's disease Summary

High-dose therapy followed by autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PSCT) is now accepted therapy for patients with relapsed Hodgkin's disease [1-7]. However, some patients with relapsed Hodgkin's disease are cured with conventional salvage chemotherapy [8, 9]. Therefore, the use of transplantation may be delayed because of uncertainty regarding efficacy, as well as concerns about expense, morbidity, and mortality. The best results of conventional salvage chemotherapy for relapsed Hodgkin's disease are seen following relapse from the initial chemotherapy-induced complete remission. Reports of transplantation for relapsed Hodgkin's disease have often included patients with more extensive prior therapy. We have examined the results of transplantation in patients who relapsed after an initial chemotherapyinduced complete remission. Since this is the situation where the best results of conventional salvage chemotherapy have been noted, this might provide a more valid comparison of conventional salvage chemotherapy results with those of ABMT and PSCT. Furthermore, this analysis could help to define the optimal

timing of ABMT or PSCT for patients with relapsed Hodgkin's disease. Patients and methods Records were reviewed of patients at the University of Nebraska Medical Center who received ABMT or PSCT for Hodgkin's disease between October, 1984 and June, 1992. Patients were selected for this study if they had relapsed after achieving a first complete remission with combination chemotherapy. Thirteen (15%) patients have been previously described [5]. Most patients received a planned short course of conventional-dose salvage chemotherapy (median 2 cycles) to decrease tumor bulk immediately prior to their high-dose chemotherapy. The most common salvage chemotherapy consisted of dexamethasone, cytarabine, and cisplatin (DHAP, n - 35). Most other patients received a MOPP-type regimen or an ABVD-type regimen1 depending on their initial therapy. Following transplantation, 22 (26%) patients received 2000-4000 cGy involved-field radiation to sites of prior disease. This too, was considered to be a component of the transplant procedure. Protocols were approved by the Institutional Review Board and informed consent was obtained from all patients prior to transplantation. Entry criteria required a cardiac ejection fraction >50% predicted and a carbon monoxide diffusing capacity >50% predicted. Normal hepatic and renal function were required unless dysfunction could be attributed to Hodgkin's disease. Patients were required to have a bone marrow biopsy performed before bone marrow harvest that demonstrated >20%-25% eel-

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Introduction

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Response evaluation Staging evaluation was done prior to transplantation, and at three to six months following transplantation. A complete response (CR) was defined as disappearance of all clinical and radiographic evidence of disease for at least one month after transplantation. Patients with small residual radiographic abnormalities which did not progress for six months after transplantation were also classified as CR. Patients with previously abnormal gallium scans were required to have negative gallium scans to be classified as CR Partial response (PR) was defined as >50% reduction in the surface area of measurable disease for at least one month. Early death (ED) was defined as death occurring during the actual transplant hospitalization. All other patients were classified as having no response to transplantation. Statistical methods Transplant outcome was analyzed with respect to overall survival and failure-free survival. Survival time was defined as time from transplant until death from any cause or until last follow-up. Failurefree survival time was defined as time from transplant until relapse from CR, disease progression, death from any cause, or until last follow-up if none of these events had occurred. Survival times and failure-free survival distributions were calculated using the productlimit method of Kaplan and Meier [11]. Comparisons of these time to event distributions were made using the log-rank test [12].

Results Characteristics of the 85 patients in this analysis are displayed in Table 1. All patients had achieved a CR with MOPP-type chemotherapy, ABVD, or MOPP/ ABV(D)-type chemotherapy.1 Twelve patients had relapsed following radiation therapy prior to their initial chemotherapy treatment.

Table 1. Patient characteristics (n — 85). Age in years Median 30 Range 15-55 Gender Male 46 Female 39 Hematopoietic rescue source Autologous bone marrow 54 Autologous peripheral stem cells 31 Time from first chemotherapy until relapse <18 months 42 >18 months 43 First chemotherapy MOPP (or similar) 34 ABVD 8 MOPP/ABV (D) 43 Initial stage IV 20 I-UI 65 12 Prior use of definitive radiotherapy Initial use of combined modality therapy 36 Disease status at time of transplant Sensitive relapse 47 Resistant relapse 21 Not tested 9 Not evaluable 8

Following transplantation 56 (66%) patients were in CR, 19 (22%) patients achieved PR, and 7 (8%) patients had no response. There were 3 (4%) early deaths. Causes of early death were Streptococcal sepsis, diffuse alveolar hemorrhage, and cardiac tamponade in one patient each. Currently 47 patients are alive between 26 months and 119 months (median 54 months) following transplantation. Thirty-three patients are alive and failure-free between 26 months and 119 months (median 58 months) following transplantation. Five patients died between three and 92 months following transplant without evidence of treatment failure. Causes of death in these patients were suicide, sepsis, intracranial bleeding, non-Hodgkin's lymphoma, and myelodysplastic syndrome (MDS). The patient with MDS died 92 months after transplantation. One other patient developed MDS following relapse of Hodgkin's disease and died 39 months following transplantation. Seven patients relapsed more than two years from the time of transplantation at 25,25,26, 31,43,53, and 68 months. Overall survival and failure-free survival are displayed in Figure 1. At five years after transplantation, overall survival is projected to be 51% (95% CI, 39% to 64%) and failure-free survival is projected to be 40% (95% CI, 29% to 51%). Transplant outcome was evaluated with respect to the variables noted in Table 1. Failure-free survival for patients who relapsed at least 18 months after starting primary chemotherapy was estimated to be 47% (95% CI, 32% to 63%) at five years, compared with 32% (95% CI, 18% to 47%) for patients with shorter remissions (p - 0.16; Figure 2). Overall survival was projected to be 44% (95%

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lularity without histologic evidence of tumor involvement. Bone marrow was harvested during general anesthesia, preserved in 10% dimethylsulfoxide (DMSO), and then frozen at a controlled rate or else preserved in 5% DMSO and 6% hydroxyethyl starch and immediately frozen at -130'C. During the latter period of patient accrual PSCT rather than ABMT was performed for patients with any history of marrow metastasis or for patients whose marrow could not be harvested because of hypocellularity or prior radiation. Details of peripheral stem cell collection have previously been reported [10]. Some patients received granulocyte-macrophage colony stimulating factor or granulocyte colony stimulating factor to increase the numbers of circulating progenitor cells during apheresis. Peripheral stem cells were preserved in 10% DMSO and frozen at a controlled rate, or preserved in 5% DMSO and 6% hydroxyethyl starch and frozen at -130 "C. All patients were transplanted with the CBV regimen consisting of cyclophosphamide 1500 mg/m2 daily for four days (day - 6 to day —3), carmustine 300 mg/m2 on day - 6 , and etoposide 100-125 mg/ m2 every 12 hours for three days (day —6 to day —4). Patients were treated in private rooms, usually with high efficiency paniculate air filtration. Mesna or indwelling urinary catheters with continuous bladder irrigation was used to prevent hemorrhagic cystitis. Empiric antibiotic therapy was given according to various institutional protocols in place during the period of patient accrual. Starring in April, 1991 granulocyte-macrophage colony stimulating factor was used to accelerate myeloid recovery following transplant Platelet transfusions were given to keep platelet counts >20,000/ul and packed red blood cell transfusions were given to keep hemoglobin levels >9-10 g/dl. All blood products were irradiated prior to transfusion.

153 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

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Figure 1. Overall survival ( all 85 patients.

1.017

), and failure-free survival (—), for

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Figure 2. Failure-free survival for 43 patients who relapsed >18 months after starting initial chemotherapy (—), and for 42 patients relapsing < 18 months after starting initial chemotherapy (—).

CI, 27% to 61%), and 59% (95% a , 41% to 76%) at five years for patients with short and long initial remissions, respectively (p = 0.17). Ten patients received no conventional-dose debulking chemotherapy after relapse and proceeded directly to transplantation. Characteristics of these patients are displayed in Table 2. Failure-free survival for these patients was projected to be 90% (95% CI, 71% to 99%) at five years, compared with 33% (95% a , 22% to 44%) for the remaining patients who received Table 2. Characteristics of patients who did not receive conventional salvage therapy before CBV. PL no.

Disease status at transplant

Length of initial remission (months)

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4 cm adenopathy Minimal Minimal Minimal Bone marrow only 4 cm adenopathy Minimal Minimal 4 cm adenopathy Minimal

<18 >18 >18 <18 <18 >18 >18 <18 >18 <18

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Figure 3. Failure-free survival for 10 patients who received CBV immediately after relapse (—), and for 75 patients who received a short course of conventional-dose salvage chemotherapy before receiving CBV (—).

Discussion Although large numbers of patients with relapsed Hodgkin's disease are being treated with high-dose therapy followed by transplantation, the optimal timing for this procedure is uncertain. Many physicians have been reluctant to use transplantation after relapse from a single chemotherapy-induced complete remission because of the potential for cure with conventional salvage chemotherapy, particularly when initial remissions are prolonged. Patients who have relapsed from a MOPP-induced complete remission can often achieve a second CR if retreated with MOPP. At the National Cancer Institute, a 93% second CR rate was seen in patients with initial remissions longer than 12 months, compared with 29% for patients with shorter remissions [14]. However, follow-up results showed that only 17% of these patients were projected to be alive at 20 years [15]. The Cancer and Leukemia Group B reported a projected failure-free survival of 15% at five years for patients treated with ABVD after failing MOPP [16]. Patients treated initially with ABVD and switched to MOPP had an estimated failure-free survival of 31% at five years. The best results of conventional salvage therapy for Hodgkin's disease have been reported by investigators from Milan [17-19]. Freedom from progression atfiveyears was 51% for patients with initial remissions longer than one year following MOPP, ABVD, or MOPP/ABVD [17]. However, patients who died from

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conventional chemotherapy prior to transplantation (p - 0.016; Figure 3). Overall survival at five years for these groups was projected to be 100% and 45% (95% Q , 32% to 58%), respectively (p = 0.048). No difference in failure-free survival was noted between patients initially treated with MOPP-like regimens, ABVD, or MOPP/ABV(D). Similarly, gender, age, relapse after initial definitive radiation, and rescue product did not influence overall survival or failurefree survival.

154 less expensive, and analyses should be repeated with results obtained from patients transplanted after first relapse. Most patients undergoing transplantation for relapsed Hodgkin's disease receive a short course of conventional salvage chemotherapy prior to their highdose therapy regimen. This therapy may provide prognostic information, and may improve the results of transplantation by reducing tumor burden [3-6, 24]. The patients who were transplanted without receiving conventional debulking therapy had a significantly better outcome than those who received debulking therapy. Although these patients were selected, three patients had significant adenopathy at the time of transplantation, one patient had bone marrow involvement, and five had initial remissions of short duration. Similar results were seen by the London group, who noted a 78% five-year progTession-free survival for patients transplanted in untested relapse [3]. A trial from Seattle failed to show a benefit from high-dose cyclophosphamide prior to autologous stem cell transplantation [25]. The results of allogeneic transplantation for acute myelogenous leukemia in early untreated first relapse are similar to those achieved for second remission patients [26]. It may also be appropriate to transplant some Hodgkin's disease patients in early relapse, especially those with minimal tumor burden. While some reports have suggested that patients who fail seven/eight-drug Hodgkin's disease chemotherapy regimens are more resistant to salvage therapy than those who fail four-drug regimens [18, 23], others have not [15,19]. We found no significant differences between patients who relapsed after MOPP-type regimens, ABVD, or seven/eight-drug regimens. We identified seven late relapses including one patient who relapsed 68 months after transplantation. Late relapses following autologous transplantation for Hodgkin's disease have been described previously [1-3, 5, 7]. In addition, two patients developed MDS following transplantation. This complication has also been described following autologous transplantation for Hodgkin's disease [27]. These events mandate continued follow-up for patients transplanted for Hodgkin's disease. There is increasing evidence that salvage therapy for Hodgkin's disease using high-dose therapy followed by ABMT or PSCT is superior to conventional salvage chemotherapy [28, 29]. Most investigators now recommend transplantation for Hodgkin's disease patients who fail to enter complete remission with primary chemotherapy, those who fail two or more chemotherapy regimens, and those who relapse within one year after primary chemotherapy. These results, and others, demonstrate that failure-free survival following transplantation for Hodgkin's disease patients with long initial remissions may also be better than those reported for conventional salvage chemotherapy. However, it cannot be shown that overall survival is improved with this approach. We continue to recommend transplanta-

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second malignancies or cardiopulmonary disease were censored. After initial remissions of less than one year following MOPP, salvage therapy with ABVD resulted in a 65% CR rate and 35% probability of remaining disease-free at five years [18]. Patients with initial remissions longer than 12 months after MOPP/ ABV(D) had a 46% freedom from progression at five years, compared with 22% for patients with shorter remissions [19]. Results from other institutions have generally been inferior [8, 9]. It is unclear whether newer conventional salvage regimens will improve results [20, 21]. We analyzed results of transplantation for Hodgkin's disease patients in first relapse as a way of comparing this approach to the best results of conventional salvage chemotherapy. Investigators from Milan and the National Cancer Institute defined remission duration as the interval from the end of chemotherapy until relapse. Since the duration of chemotherapy administration is variable, we defined a long initial remission as at least 18 months between the date chemotherapy was started and the date of relapse. Our results will not differ from other institutions for patients who receive six months of chemotherapy. However, a patient who relapsed within one year of completing a primary chemotherapy regimen of longer duration would be included in the short remission group at other institutions, but the long remission group in this series. Chopra et al. reported a 47% progression-free survival at five years following transplantation for Hodgkin's disease in first relapse [3]. Patients with initial remissions of more than 12 months had a progression-free survival estimated at 57% compared with 41% for patients with shorter remissions. The Vancouver group reported an actuarial progression-free survival of 64% for a similar cohort [22]. Patients with initial remissions of less than one year had progressionfree survival estimated to be 48% compared with 85% for those with longer remissions. The Milan group noted that freedom from second progression was 76% following transplantation for patients who relapsed within one year of MOPP/ABVD [18]. At City of Hope, a 2-year disease-free survival of 76% was observed for patients in first relapse or second complete remission when initial remission duration was at least one year [7]. Our results, as well as others [3, 7, 18, 22], indicate that high-dose therapy with ABMT or PSCT for Hodgkin's disease patients in first relapse yields superior freedom from second progression compared with most results reported with conventional salvage chemotherapy. The issue of selection bias cannot be ignored; however, few patients referred for transplantation at our institution failed to proceed to transplantation. A decision analysis suggested that Hodgkin's disease patients who relapse after a short remission might benefit most from conventional therapy and that transplantation should be reserved for second relapse [23]. However, transplantation has become safer and

155 tion for all Hodgkin's disease patients who have relapsed or failed any primary chemotherapy regimen, regardless of the length of initial remission. Continued efforts are necessary to improve the results of transplantation. Such efforts might include the use of purging, improvements in preparative regimens, or additional therapy after transplantation. As the safety of allogeneic transplantation improves, this technique will need to be examined as an alternative to autologous transplantation.

Acknowledgements

Note 1. MOPP-type chemotherapy - MOPP: mechlorethamine, vincristine, procarbazine prednisone; ChlVPP: chlorambucil, vinblastine, procarbazine, prednisone; MVPP: mechlorethamine, vinblastine, procarbazine, prednisone; TVB: thiotepa, vinblastine, bleomycin; COPP: cyclophosphamide, vincristine, procarbazine, prednisone; BVPP: carmustine, vinblastine, procarbazine, prednisone; or BCVPP: cannustine, cyclophosphamide, vincristine, procarbazine, prednisone. ABVD - doxombicin, bleomycin, vinblastine, dacarbazine. MOPP/ABV(D)-type chemotherapy - MOPP and ABVD administered in alternating or sequential fashion, or as a hybrid regimen [13], COPP alternating with ABVD, or MOP-BAP: mechlorethamine, vincristine, procarbazine, bleomycin, doxorubicin, prednisone.

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This work was supported in part by TJSPHS CA36727, awarded by the National Cancer Institute, Department of Health and Human Services. The authors would like to thank Jene Pierson and Martin Bast for their assistance in the preparation of this manuscript.

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conventional salvage therapy for recurrent or refractory Hodgkin's disease. Blood 1994; 10 (Suppl 1): 234a. Received 9 November 1995; accepted 16 January 1996. Correspondence to: Philip J. Bierman, MX). University of Nebraska Medical Center 600 S. 42nd St. Omaha, NE 68198-3330, U.SA.

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