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High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease: Long term follow-up in 128 patients
Annals of Oncology 4: 767-773, 1993. © 1993 KUcwer Academic Publishers. Printed in the Netherlands.
Original article High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease: Long term follow-up in 128 patients PJ. Bierman,1 R.G. Bagin,2 S. Jagannath,3 J.M. Vose,1 G. Spitzer,3 A. Kessinger,1 KA. Dicke 3 & J.O. Armitage1 'Department of Internal Medicine and 2 Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; ^Department of Hematology, M.D. Anderson Cancer Center, Houston, TX, U.S.A.
Relapses more than 24 months after transplantation were seen in 11 patients. Five patients developed myelodysplastic Background: There is little long term follow-up information syndromes. Three patients became pregnant after the transafter autologous transplantation for Hodgkin's disease. We plant. evaluated the influence of various prognostic factors and Conclusions: Prolonged failure-free survival may be obexamined the outcome in 128 such patients. served following high dose chemotherapy and autologous Patients and methods: Patients received high dose cyclo- hematopoietic rescue in patients with Hodgkin's disease. phosphamide, carmustine, and etoposide followed by auto- Superior results were seen in patients without extensive prior chemotherapy and in those with a good performance status. logous hematopoietic rescue. Results: Patients have been observed between 50-130 Late relapses and deaths from secondary myelodysplastic months (median 77 months) following transplantation. Over- syndromes mandate prolonged follow-up after autologous all survival at four years is estimated as 45 percent, and fail- transplantation for Hodgkin's disease. ure-free survival as 25 percent. The best results were seen in patients with a good performance status, who had failed Key words: bone marrow transplantation, Hodgkin's disat most one prior chemotherapy regimen. Failure-free surviv- ease, late complications, peripheral stem cell transplantation, al at four years is estimated as 53 percent for this group. prognostic factors Summary
Introduction
At least fifty percent of patients with advanced Hodgkin's disease can now expect to be cured with initial chemotherapy [1-4]. However, approximately 25 percent of patients will not attain an initial remission, and one-third of patients who achieve an initial complete remission will relapse. Unfortunately, only a minority of these patients can expect to be cured with conventional salvage chemotherapy [5-7]. These results have led to the increasing use of high dose therapy followed by autologous bone marrow transplantation (ABMT) [8-17] and peripheral blood progenitor cell transplantation (PSCT) for patients with Hodgkin's disease [18,19]. Although ABMT and PSCT are being used with increasing frequency for patients with Hodgkin's disease, many studies have been limited to short periods of follow-up or by the inclusion of only small numbers of patients. This has made it difficult to form conclusions regarding the optimal timing of transplantation. Similarly, there is little information on the long term followup of patients who have undergone transplantation for Hodgkin's disease. This report examines the influence of pre-transplant prognostic factors and evaluates
long term follow-up in a group of 128 patients with Hodgkin's disease. Patients and methods All patients in this study had a histologjc diagnosis of Hodgkin's disease and were refractory to primary therapy, or had relapsed after attaining a remission. Patients were transplanted at the University of Nebraska Medical Center (UNMC) or the M.D. Anderson Cancer Center (MDAH). Transplant protocols were approved by the Institutional Review Boards at each institution. Entry criteria required adequate cardiac, pulmonary, hepatic and renal function. Bone marrow was harvested under general anesthesia and then frozen at a controlled rate in ten percent dimethyl sulfoxide (DMSO). Peripheral blood progenitor cells were collected by means of apheresis and frozen at a controlled rate in ten percent DMSO [19]. All patients were transplanted with the CBV regimen [20] consisting of cyclophosphamide (1500 mg/m2 x 4), carmustine (300 mg/m2), and etoposide (100-150 mg/m2 x 6). The dose of etoposide was escalated during the study period and patients received a total of 600-900 mg/m2 (Table 1). One patient received 450 mg/m2 of etoposide as part of a pilot protocol. All patients were nursed in private rooms with high efficiency air filtration, or in some cases, laminar air flow. Empiric antibiotic therapy was given according to protocols in place at each institution. Platelet transfusions were used to keep platelet counts >20,000/nL and packed red blood cell transfusions were administered to keep
768 hemoglobin levels >9.0 gm/dL. Blood products were irradiated prior to transfusion.
tients had relapsed from at least one chemotherapy regimen. Fifteen patients were transplanted solely with peripheral blood progenitor cells. Twelve of these pa-
Response evaluation A complete response (CR) was defined as the disappearance of all clinical and radiographic evidence of disease for at least one month following transplantation. Patients with small residual radiographic abnormalities which did not progress for six months after transplantation were classified as having attained CR Patients who were transplanted without evidence of disease were not evaluable for response to CBV and were considered to be in continuous complete remission (CCR) following transplantation. A partial response (PR) was defined as >50 percent reduction of the surface area of all measurable disease for at least one month following transplantation. Early death (ED) was defined as death occurring during the actual transplant hospitalization. All other patients were classified as having had no response to transplantation.
Statistical methods The Pearson chi-square statistic was used to detect differences in the distribution of categorical variables between patient subgroups. Survival time was defined as the number of months from transplant until death from any cause, or until the time of last follow-up. Failure-free survival time was defined as the number of months from transplant until disease progression, relapse, or death, for those patients who achieved CR or PR following transplantation. Non-responding patients and those who had early death were considered to have failed immediately following transplantation. Overall survival and failure-free survival time distributions were estimated using the method of Kaplan and Meier [21]. Comparisons of time to event distributions were made using the log-rank test. Univariate analyses of overall survival and failure-free survival were performed with respect to: institution performing the transplant; age; gender; Ann Arbor stage at time of transplant [22|; ECOG performance status at time of transplant [23]; number of chemotherapy regimens failed prior to transplant; dose of etoposide in CBV; hematopoietic rescue source; presence or absence of mediastinal disease at any time prior to transplant; prior radiation therapy; prior mediastinal radiation therapy; size of mediastinal mass at time of transplant; extent of abdominal disease at time of transplant, and the number of extranodal sites of disease at time of transplant. The number of chemotherapy regimens failed refers to the number of regimens from which a patient relapsed or achieved less than a partial response. If a patient responded to a short course of conventional chemotherapy administered immediately prior to CBV, this was not counted as a failed regimen. The independent contributions of factors found to be significantly associated with transplant outcome in the univariate analyses were assessed using the proportional hazards model of Cox [24]. Reported p-values for these models are based on the likelihood ratio chi-square statistic.
Results
Table I. Patient characteristics. No. Transplant location MDAH UNMC Median age Gender Male Female Stage at transplant NED I 11 III
rv
Performance status at transplant 0 1 2 3 Number of chemotherapy regimens failed 0 1 2 3 4 5 6 Etoposide dose (mg/m2) 600 750 900 Hematopoietic rescue BM PSC BM + PSC Prior mediastinal disease Never Ever Prior radiation therapy Never Relapse outside field Relapse in field Prior mediastinal radiation Never Mediastinal relapse Non-mediastinal relapse Mediastinal disease at transplant None <7.5 cm >7.5 cm Abdominal disease at transplant None <5 cm >5cm Extranodal sites at transplant 0 1 >2
%
60 68 28
47 53 range 11-57
78 50
61 39
9 14 22 15 68
7 11 17 12 53
55 65 6 2
43 51 5 2
1 34 45 24 16 3 5
1 27 35 19 13 2 4
23 35 69
18 27 54
109 15 4
85 12 3
24 104
19 81
37 23 68
29 18 53
49 27 52
38 21 41
59 52 17
46 41 13
89 70 Between September 18,1978 and December 24,1987, 19 15 128 patients were transplanted (Table 1). Follow-up for 20 16 surviving patients is between 50 and 130 months (median 77 months). Nine patients were transplanted 58 45 55 43 in second or subsequent remission. These patients are 15 12 not evaluable for response to CBV, but are included in the survival analysis. A single patient received CBV in MDAH: M.D. Anderson Cancer Center, UNMC: University of first partial remission and is considered to have failed Nebraska Medical Center; NED: No evidence of disease; BM: zero regimens prior to transplantation. All other pa- Bone Marrow; PSC: Peripheral Blood Progenitor Cells.
769
Prognostic factors
No differences in overall survival or failure-free survival were identified between patients transplanted at UNMC or MDAH. Therefore, patients from both institutions were combined for all analyses. No differences in either outcome were observed between patients receiving various doses of etoposide, and these patients were not considered separately. Results of the univariate analysis of prognostic factors are displayed in Table 2. Stage of disease at transplant, performance status, number of chemotherapy regimens failed, hematopoietic rescue source, and prior mediastinal radiation were found to be significantly associated with overall survival at the a = 0.05 level. Performance status, number of chemotherapy regimens failed, and the presence of mediastinal disease at the time of transplant were significantly associated with failure-free survival. The failure-free survival curve,
1.0 0.9 \ 0.8
\
0.7 CO
srcen t Survlv
tients had evidence of bone marrow involvement at the time of transplant, while three patients had received prior pelvic radiation. Four patients received autologous bone marrow supplemented with peripheral blood progenitor cells as part of a trial to test whether this would accelerate engraftment. These patients were analyzed with the patients who received bone marrow alone. Following transplantation, 57 (45%) patients achieved CR with the CBV regimen. Nine (7%) patients who were transplanted without evidence of disease continued in remission following the transplant (CCR). Seven (5%) patients received localized radiation following transplantation to areas of apparent residual disease. This radiation was considered to be part of the whole treatment process and was able to convert these patients to CR In total, 73 (57%) patients were in CR following transplantation, twenty-three (18%) patients achieved a PR, and 21 (16%) had no response. There were 11 (9%) early deaths. Causes of early death included interstitial pneumonitis/diffuse alveolar hemorrhage [25] in seven patients, Candida sepsis in two patients, cardiac tamponade in one patient, and gram negative sepsis in one patient. Among the 73 patients in CR following CBV treatment, 34 have subsequently died, including six who died without evidence of disease between six and 59 months following transplantation. The causes of death in these six patients were coccidioidomycosis in one patient, pulmonary fibrosis in one patient, bacterial pneumonia in three patients, and idiopathic pneumonitis in one patient. Currently 43 patients are alive, including 28 who remain free from progression. The median survival time for the entire patient group is 31.5 months, and the median failure-free survival time is 7.3 months. The estimated four year overall survival is 45% (95% CI, 36% to 53%), and the four year failurefree survival is estimated as 25% (95% CI, 17% to 33%) (Fig. 1).
0.6 0.5- \
\ L
0.4
Q.
\
• 1 1 II IHII
1 H
1
L
0.3
1L
0.2
>_ILUttL JJitU_Ui
1
0.1 00
20
40
60
80
100
120
140
Months Fig. I. Overall survival ( ) and failure-free survival ( 128 patients transplanted for Hodgkin's disease.
) for
Table 2. Univariate analysis of prognostic factors.
Stage I, II III, IV Performance Status (ECOG) 0 1-3 No. Chemos failed 0-1 0-2 >2 Rescue BM
PSC Prior mediastinal radiation No Yes Mediastinal disease at transplant No Yes
Survival
Failure-free survival
0.005
NS
0.004
0.001
0.030
0.049
0.012
0.023
0.030
0.107
0.023
NS 0.050
stratified by the number of chemotherapy regimens failed is displayed in Fig. 2. The four year failure-free survival for patients with at most one failed chemotherapy regimen prior to transplantation is estimated as 37 percent (95% CI, 21% to 53%), patients with two failed chemotherapy regimens have an estimated four year failure-free survival of 31 percent (95% CI, 17% to 45%), and those with more than two failed chemotherapy regimens have an estimated four year failure-free survival often percent (95% CI, 2% to 19%).
770 1.0 0.9 0.8
'cent Failtire-Fi
0.7-
a
0.6 0.50.4 0.3
'"•S.JI..II.. LJ
jjg
i
0.20.1 0.0-I 20
40
60
80
100
120
140
Months Fig. 2. Failure-free survival for patients with <1 failed chemotherapy regimen prior to transplantation ( ), those with 2 failed regimens prior to transplantation (••••)> a n d those with > 2 failed regimens prior to transplantation ( ).
Rescue source was significantly associated with overall survival but only marginally associated with failure-free survival in the univariate analyses (Table 2). Patients receiving PSCT had significantly poorer survival than ABMT patients. However, eighty-seven percent of PSCT patients had poor performance status compared to 53 percent of the ABMT patients and ninety-three percent of PSCT patients had failed more than one prior chemotherapy regimen compared to 70 percent of ABMT patients. Because of these confounding conditions in this small group of patients, rescue source was not included in the multivariate analyses. The independent effects of the variables found to be significantly associated with survival and failure-free survival in the univariate analyses were assessed in a
stepwise fashion after first controlling for the number of previous chemotherapy regimens failed (Table 3). When patients were first classified as to whether or not they had failed at most one prior chemotherapy regimen, only performance status was found to be significantly associated with survival (p = 0.013) and failurefree survival (p = 0.035). For patients failing no more than one previous chemotherapy regimen, the estimated four year failure-free survival is 53 percent (95% CI, 29% to 77%) for patients with a good performance status (ECOG 0), and 22 percent (95% CI, 3% to 42%) for patients with poorer performance status (Fig 3). Similarly, when patients were first classified as to whether or not they had failed at most two prior chemotherapy regimens, only performance status was found to be significantly associated with survival (p = 0.012) and failure-free survival (p — 0.045). For patients failing no more than two prior chemotherapy regimens, the estimated four year failure-free survival is 47 percent (95% CI, 31% to 64%) for good performance status patients, and 21 percent (95% CI, 9% to 34%) for poor performance status patients (Fig. 4). Complete remission durability Seven patients who were thought to have achieved only a PR after transplantation were given additional involved-field radiation after the transplant and attained a CR. Nine patients transplanted without clinical evidence of disease survived the transplant and continued in complete remission (CCR). Among the 119 patients transplanted with evidence of active disease, 57 (48%) achieved CR. No significant difference in failure-free survival (p — 0.44) was found for patients in complete remission following transplantation, regardless of how the remission was achieved. Late relapses
Eleven patients relapsed between 24 and 74 months following transplantation. Patients with late relapses were more likely to have fewer extranodal sites of dis-
Table 3. Multivariate models for survival and failure-free survival controlling for previous chemotherapies failed. Risk Ratio" for Failure
Risk Ratio" for Death
Model 1 Previous Chemos. Performance Status 0, 1+ Model 2 Previous Chemos. <2,>2 Performance Status 0,1 +
Estimate
95% CI
p-value
Estimate
95% CI
p-value
2.17
0.99-4.74
0.052
2.22
0.96-5.24
0.068
2.29
1.19-4.41
0.013
2.17
1.06-4.46
0.035
2.07
1.11-3.88
0.022
2.20
1.07-4.52
0.031
2.29
1.20-4.37
0.012
2.08
1.02-4.26
0.045
* Represents the increased risk of either death or failure for the category in bold relative to the unbolded category for each variable.
771 relapse, while five patients with late relapses remain alive between five and 50 months after relapse.
1.0n 0.9
Secondary Malignancies 0.8
I To u.
0.5
0)
0.4
Five patients developed a myelodysplastic syndrome (MDS) following transplantation. The time from transplant to the development of a secondary MDS ranged between 12 and 79 months. Two patients had relapsed following transplantation at the time their MDS was diagnosed, while three were still in remission. All five patients died within one year of development of MDS.
0.3
Pregnancy
o
u
a> a.
0.7 0.6
0.2
"i—:-.-
0.1 0.0-I 20
40
60
80
100
120
140
Months Fig. 3. Failure-free survival for patients with <1 failed chemotherapy regimen and performance status 0 ( ), < 1 failed regimen and performance status 1+ ( • • • • ) , >1 failed regimen and performance status 0 ( ), and >1 failed regimen and performance status l + ( ).
Three women in this series became pregnant. One woman delivered a healthy child from a donated ovum 83 months following transplantation. Another woman, who used ovulatory stimulating agents, became pregnant with twins. She had a spontaneous abortion at 5 1/2 months gestation, 72 months following transplantation. A third woman delivered a healthy child 72 months following transplantation. No ovulatory stimulating agents were utilized.
Discussion 1.0
This report includes patients previously described [8, 9] and extends our preliminary observations on this co0.9 hort of 128 patients [26]. Patients with a good performance status, who had failed at most one chemother0.8 apy regimen prior to transplantation had the best prognosis (Fig. 3). In contrast, the four year failure-free 0.7 survival is estimated as six percent for more heavily treated patients with a poor performance status (Fig. 0.6 4). The negative influence of extensive prior chemo« 0.5 therapy and poor performance status on outcome following ABMT for Hodgkin's disease has previously 0.4 been reported [9,10,14,15]. Nevertheless, these results do not define the optimal 0.3 time for transplantation in Hodgkin's disease since conventional salvage chemotherapy [5-7], and radiation 0.2 therapy [27] may cure some patients. The best results of conventional salvage chemotherapy have been report0.1 ed by the Milan group who noted a freedom from second progression of 51 percent in patients who had 0.0 60 80 40 20 100 120 140 relapsed after an initial remission of at least 12 months [28]. Most reports of conventional salvage chemotherMonths apy are inferior to those reported by the Milan group, Fig. 4. Failure-free survival for patients with < 2 failed chemohowever [5-7]. Analysis from Vancouver suggests that therapy regimens and performance status 0 ( ), <2 failed regimens and performance status 1+ ( • • • • ) , > 2 failed regimens and the outcome of salvage therapy for relapsed Hodgkin's performance status 0 ( ), and >2 failed regimens and perfordisease is dependent on the duration of initial remismance status 1+ ( ). sion, the initial stage of disease, and the presence of systemic symptoms at relapse, rather than on any speease at the time of transplant than those who relapsed cific type of salvage therapy [29]. A decision analysis within the first two years (85% <1 site vs. 53% <1 site, suggests that patients who relapse following MOPP p - 0.028). Six patients with late relapses died of pro- should be treated with conventional salvage chemogressive disease between four and 45 months following therapy first, and that transplantation should be re-
772
served for patients who fail salvage chemotherapy [30]. Factors such as initial remission duration [18, 29], as well as other differences in prognostic variables make it difficult to compare our results with others. The optimal timing of transplantation may only be resolved with prospective trials. Nonetheless, our results in patients who had received only one chemotherapy regimen are better than most results reported for conventional salvage chemotherapy. Since most patients with Hodgkin's disease fail to attain durable remissions with conventional salvage therapy we recommend transplantation following failure of any front-line chemotherapy regimen. Seven patients in this series received post-transplant radiation to areas of apparent residual disease. The remission durability of these patients is similar to that of patients in complete remission at the time of transplantation, and to that of patients who achieved CR with the high dose chemotherapy alone. The use of post-transplant radiotherapy to convert patients into complete remission has been reported by others [12, 16]. The long term outlook for patients following autologous transplantation for Hodgkin's disease is less clear in light of the late relapses we observed. The European Bone Marrow Transplant Group reported a relapse in a patient more than six years following ABMT for Hodgkin's disease [31]. Reece et al. [10] described relapses at 40 and 42 months after ABMT, Phillips et al. [15] described four relapses between 3.3 and 4.5 years following ABMT, and investigators from Royal Marsden Hospital noted a relapse occurring 29 months following ABMT [17]. Patients in this and other reported series are still at risk for relapse. Prolonged follow-up and updated results of previously reported series will help to determine the actual long term outcome of patients following ABMT and PSCT for Hodgkin's disease. Five patients in this series developed myelodysplastic syndromes. Acute myelogenous leukemia and MDS have only been described infrequently following ABMT for Hodgkin's disease [13, 16, 32]. The occurrence of MDS in our patients is most likely related to initial treatment with MOPP chemotherapy [33]. Like other patients with secondary MDS, patients in this series had an extremely poor prognosis. Three patients became pregnant following transplantation. Successful pregnancies have been described following allogeneic bone marrow transplantation [34, 35]. Pregnancy following ABMT has been described less frequently. Premature ovarian failure is common following MOPP chemotherapy [36]. The women who became pregnant in this series had all received MOPP, but all had received this treatment, as well as transplantation, prior to the age of 25. The fact that pregnancy is possible following autologous transplantation with the CBV regimen is valuable with regard to pre-transplant patient counseling. This report demonstrates that long term failure-free
survival is possible following transplantation for Hodgkin's disease. Ultimately, only a relatively small percentage of patients will benefit from transplantation and efforts to improve these results are necessary. Such efforts might include the use of new preparative regimens, dose escalation of existing regimens, tandem transplantation, or adjuvant therapy following transplantation. The use of transplantation may have the biggest impact on outcome in Hodgkin's disease if used as part of the initial therapy. Preliminary data suggest that transplantation used as consolidation therapy for certain patients in first remission may improve results over those of similar patients treated with chemotherapy alone [37].
Acknowledgment
We thank Jene Pierson for assistance in the preparation of this manuscript. Note added in proof
Recently, Chopra et al. (Blood 1993; 81: 1137-45) have reported the development of myelodysplastic syndromes in two patients following ABMT for Hodgkin's disease as well as pregnancy in two patients following ABMT for Hodgkin's disease.
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26. Bierman PJ, Jagannath S, Dicke KA et al. High dose cyclophosphamide, carmustine, and etoposide (CBV) in 128 patients (PTS) with Hodgkin's disease (HD). Blood 1988; 72 (Suppl 1): 239a. 27. Brada M, Eeles R, Ashley S et al. Salvage radiotherapy in recurrent Hodgkin's disease. Ann Oncol 1992; 3: 131-5. 28. Viviani S, Santoro A, Negretti E et al. Salvage chemotherapy in Hodgkin's disease. Ann Oncol 1990; 1: 123-7. 29. Lohri A, Barnett M, Fairey RN et al. Outcome of treatment of first relapse of Hodgkin's disease after primary chemotherapy: Identification of risk factors from the British Columbia experience 1970 to 1988. Blood 1991; 77: 2292-8. 30. Desch CE, Lasala MR, Smith TJ et al. The optimal timing of autologous bone marrow transplantation in Hodgkin's disease patients after a chemotherapy relapse. J Clin Oncol 1992; 10: 200-9. 31. Green ES, Taghipour G, Goldstone AH. Report of the EBMT registry of ABMT in Hodgkin's disease: Outcome in patients followed for at least three years. Bone Marrow Transplant 1990; 5 (Suppl 2): 23. 32. Chao NJ, Nademanee AP, Long GD et al. Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin's disease. J Clin Oncol 1991; 9: 1575-9. 33. Kaldor JM, Day NE, Clarke EA et al. Leukemia following Hodgkin's disease. N Engl J Med 1990; 322: 7-13. 34. Sanders JE, Buckner CD, Amos D et al. Ovarian function following marrow transplantation for aplastic anemia or leukemia. J Clin Oncol 1988; 6: 813-8. 35. Hinterberger-Fischer M, Kier P, Kalhs P et al. Fertility, pregnancies and offspring complications after bone marrow transplantation. Bone Marrow Transplant 1991; 7: 5-9. 36. Bookman MA, Longo DL, Young RC. Late complications of curative treatment in Hodgkin's disease. JAMA 1988; 260: 680-3. 37. Carella AM, Carlier P, Congiu A et al. Autologous bone marrow transplantation as adjuvant treatment for highrisk Hodgkin's disease in first complete remission after MOPP/ABVD protocol. Bone Marrow Transplant 1991; 8: 99-103. Received 15 April 1993; accepted 22 June 1993.
Correspondence to: Philip J. Bierman, M.D. Assistant Professor of Medicine Section of Hematology/Oncology Department of Internal Medicine University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-3330 U.S.A.
Original article High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease: Long term follow-up in 128 patients PJ. Bierman,1 R.G. Bagin,2 S. Jagannath,3 J.M. Vose,1 G. Spitzer,3 A. Kessinger,1 KA. Dicke 3 & J.O. Armitage1 'Department of Internal Medicine and 2 Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; ^Department of Hematology, M.D. Anderson Cancer Center, Houston, TX, U.S.A.
Relapses more than 24 months after transplantation were seen in 11 patients. Five patients developed myelodysplastic Background: There is little long term follow-up information syndromes. Three patients became pregnant after the transafter autologous transplantation for Hodgkin's disease. We plant. evaluated the influence of various prognostic factors and Conclusions: Prolonged failure-free survival may be obexamined the outcome in 128 such patients. served following high dose chemotherapy and autologous Patients and methods: Patients received high dose cyclo- hematopoietic rescue in patients with Hodgkin's disease. phosphamide, carmustine, and etoposide followed by auto- Superior results were seen in patients without extensive prior chemotherapy and in those with a good performance status. logous hematopoietic rescue. Results: Patients have been observed between 50-130 Late relapses and deaths from secondary myelodysplastic months (median 77 months) following transplantation. Over- syndromes mandate prolonged follow-up after autologous all survival at four years is estimated as 45 percent, and fail- transplantation for Hodgkin's disease. ure-free survival as 25 percent. The best results were seen in patients with a good performance status, who had failed Key words: bone marrow transplantation, Hodgkin's disat most one prior chemotherapy regimen. Failure-free surviv- ease, late complications, peripheral stem cell transplantation, al at four years is estimated as 53 percent for this group. prognostic factors Summary
Introduction
At least fifty percent of patients with advanced Hodgkin's disease can now expect to be cured with initial chemotherapy [1-4]. However, approximately 25 percent of patients will not attain an initial remission, and one-third of patients who achieve an initial complete remission will relapse. Unfortunately, only a minority of these patients can expect to be cured with conventional salvage chemotherapy [5-7]. These results have led to the increasing use of high dose therapy followed by autologous bone marrow transplantation (ABMT) [8-17] and peripheral blood progenitor cell transplantation (PSCT) for patients with Hodgkin's disease [18,19]. Although ABMT and PSCT are being used with increasing frequency for patients with Hodgkin's disease, many studies have been limited to short periods of follow-up or by the inclusion of only small numbers of patients. This has made it difficult to form conclusions regarding the optimal timing of transplantation. Similarly, there is little information on the long term followup of patients who have undergone transplantation for Hodgkin's disease. This report examines the influence of pre-transplant prognostic factors and evaluates
long term follow-up in a group of 128 patients with Hodgkin's disease. Patients and methods All patients in this study had a histologjc diagnosis of Hodgkin's disease and were refractory to primary therapy, or had relapsed after attaining a remission. Patients were transplanted at the University of Nebraska Medical Center (UNMC) or the M.D. Anderson Cancer Center (MDAH). Transplant protocols were approved by the Institutional Review Boards at each institution. Entry criteria required adequate cardiac, pulmonary, hepatic and renal function. Bone marrow was harvested under general anesthesia and then frozen at a controlled rate in ten percent dimethyl sulfoxide (DMSO). Peripheral blood progenitor cells were collected by means of apheresis and frozen at a controlled rate in ten percent DMSO [19]. All patients were transplanted with the CBV regimen [20] consisting of cyclophosphamide (1500 mg/m2 x 4), carmustine (300 mg/m2), and etoposide (100-150 mg/m2 x 6). The dose of etoposide was escalated during the study period and patients received a total of 600-900 mg/m2 (Table 1). One patient received 450 mg/m2 of etoposide as part of a pilot protocol. All patients were nursed in private rooms with high efficiency air filtration, or in some cases, laminar air flow. Empiric antibiotic therapy was given according to protocols in place at each institution. Platelet transfusions were used to keep platelet counts >20,000/nL and packed red blood cell transfusions were administered to keep
768 hemoglobin levels >9.0 gm/dL. Blood products were irradiated prior to transfusion.
tients had relapsed from at least one chemotherapy regimen. Fifteen patients were transplanted solely with peripheral blood progenitor cells. Twelve of these pa-
Response evaluation A complete response (CR) was defined as the disappearance of all clinical and radiographic evidence of disease for at least one month following transplantation. Patients with small residual radiographic abnormalities which did not progress for six months after transplantation were classified as having attained CR Patients who were transplanted without evidence of disease were not evaluable for response to CBV and were considered to be in continuous complete remission (CCR) following transplantation. A partial response (PR) was defined as >50 percent reduction of the surface area of all measurable disease for at least one month following transplantation. Early death (ED) was defined as death occurring during the actual transplant hospitalization. All other patients were classified as having had no response to transplantation.
Statistical methods The Pearson chi-square statistic was used to detect differences in the distribution of categorical variables between patient subgroups. Survival time was defined as the number of months from transplant until death from any cause, or until the time of last follow-up. Failure-free survival time was defined as the number of months from transplant until disease progression, relapse, or death, for those patients who achieved CR or PR following transplantation. Non-responding patients and those who had early death were considered to have failed immediately following transplantation. Overall survival and failure-free survival time distributions were estimated using the method of Kaplan and Meier [21]. Comparisons of time to event distributions were made using the log-rank test. Univariate analyses of overall survival and failure-free survival were performed with respect to: institution performing the transplant; age; gender; Ann Arbor stage at time of transplant [22|; ECOG performance status at time of transplant [23]; number of chemotherapy regimens failed prior to transplant; dose of etoposide in CBV; hematopoietic rescue source; presence or absence of mediastinal disease at any time prior to transplant; prior radiation therapy; prior mediastinal radiation therapy; size of mediastinal mass at time of transplant; extent of abdominal disease at time of transplant, and the number of extranodal sites of disease at time of transplant. The number of chemotherapy regimens failed refers to the number of regimens from which a patient relapsed or achieved less than a partial response. If a patient responded to a short course of conventional chemotherapy administered immediately prior to CBV, this was not counted as a failed regimen. The independent contributions of factors found to be significantly associated with transplant outcome in the univariate analyses were assessed using the proportional hazards model of Cox [24]. Reported p-values for these models are based on the likelihood ratio chi-square statistic.
Results
Table I. Patient characteristics. No. Transplant location MDAH UNMC Median age Gender Male Female Stage at transplant NED I 11 III
rv
Performance status at transplant 0 1 2 3 Number of chemotherapy regimens failed 0 1 2 3 4 5 6 Etoposide dose (mg/m2) 600 750 900 Hematopoietic rescue BM PSC BM + PSC Prior mediastinal disease Never Ever Prior radiation therapy Never Relapse outside field Relapse in field Prior mediastinal radiation Never Mediastinal relapse Non-mediastinal relapse Mediastinal disease at transplant None <7.5 cm >7.5 cm Abdominal disease at transplant None <5 cm >5cm Extranodal sites at transplant 0 1 >2
%
60 68 28
47 53 range 11-57
78 50
61 39
9 14 22 15 68
7 11 17 12 53
55 65 6 2
43 51 5 2
1 34 45 24 16 3 5
1 27 35 19 13 2 4
23 35 69
18 27 54
109 15 4
85 12 3
24 104
19 81
37 23 68
29 18 53
49 27 52
38 21 41
59 52 17
46 41 13
89 70 Between September 18,1978 and December 24,1987, 19 15 128 patients were transplanted (Table 1). Follow-up for 20 16 surviving patients is between 50 and 130 months (median 77 months). Nine patients were transplanted 58 45 55 43 in second or subsequent remission. These patients are 15 12 not evaluable for response to CBV, but are included in the survival analysis. A single patient received CBV in MDAH: M.D. Anderson Cancer Center, UNMC: University of first partial remission and is considered to have failed Nebraska Medical Center; NED: No evidence of disease; BM: zero regimens prior to transplantation. All other pa- Bone Marrow; PSC: Peripheral Blood Progenitor Cells.
769
Prognostic factors
No differences in overall survival or failure-free survival were identified between patients transplanted at UNMC or MDAH. Therefore, patients from both institutions were combined for all analyses. No differences in either outcome were observed between patients receiving various doses of etoposide, and these patients were not considered separately. Results of the univariate analysis of prognostic factors are displayed in Table 2. Stage of disease at transplant, performance status, number of chemotherapy regimens failed, hematopoietic rescue source, and prior mediastinal radiation were found to be significantly associated with overall survival at the a = 0.05 level. Performance status, number of chemotherapy regimens failed, and the presence of mediastinal disease at the time of transplant were significantly associated with failure-free survival. The failure-free survival curve,
1.0 0.9 \ 0.8
\
0.7 CO
srcen t Survlv
tients had evidence of bone marrow involvement at the time of transplant, while three patients had received prior pelvic radiation. Four patients received autologous bone marrow supplemented with peripheral blood progenitor cells as part of a trial to test whether this would accelerate engraftment. These patients were analyzed with the patients who received bone marrow alone. Following transplantation, 57 (45%) patients achieved CR with the CBV regimen. Nine (7%) patients who were transplanted without evidence of disease continued in remission following the transplant (CCR). Seven (5%) patients received localized radiation following transplantation to areas of apparent residual disease. This radiation was considered to be part of the whole treatment process and was able to convert these patients to CR In total, 73 (57%) patients were in CR following transplantation, twenty-three (18%) patients achieved a PR, and 21 (16%) had no response. There were 11 (9%) early deaths. Causes of early death included interstitial pneumonitis/diffuse alveolar hemorrhage [25] in seven patients, Candida sepsis in two patients, cardiac tamponade in one patient, and gram negative sepsis in one patient. Among the 73 patients in CR following CBV treatment, 34 have subsequently died, including six who died without evidence of disease between six and 59 months following transplantation. The causes of death in these six patients were coccidioidomycosis in one patient, pulmonary fibrosis in one patient, bacterial pneumonia in three patients, and idiopathic pneumonitis in one patient. Currently 43 patients are alive, including 28 who remain free from progression. The median survival time for the entire patient group is 31.5 months, and the median failure-free survival time is 7.3 months. The estimated four year overall survival is 45% (95% CI, 36% to 53%), and the four year failurefree survival is estimated as 25% (95% CI, 17% to 33%) (Fig. 1).
0.6 0.5- \
\ L
0.4
Q.
\
• 1 1 II IHII
1 H
1
L
0.3
1L
0.2
>_ILUttL JJitU_Ui
1
0.1 00
20
40
60
80
100
120
140
Months Fig. I. Overall survival ( ) and failure-free survival ( 128 patients transplanted for Hodgkin's disease.
) for
Table 2. Univariate analysis of prognostic factors.
Stage I, II III, IV Performance Status (ECOG) 0 1-3 No. Chemos failed 0-1 0-2 >2 Rescue BM
PSC Prior mediastinal radiation No Yes Mediastinal disease at transplant No Yes
Survival
Failure-free survival
0.005
NS
0.004
0.001
0.030
0.049
0.012
0.023
0.030
0.107
0.023
NS 0.050
stratified by the number of chemotherapy regimens failed is displayed in Fig. 2. The four year failure-free survival for patients with at most one failed chemotherapy regimen prior to transplantation is estimated as 37 percent (95% CI, 21% to 53%), patients with two failed chemotherapy regimens have an estimated four year failure-free survival of 31 percent (95% CI, 17% to 45%), and those with more than two failed chemotherapy regimens have an estimated four year failure-free survival often percent (95% CI, 2% to 19%).
770 1.0 0.9 0.8
'cent Failtire-Fi
0.7-
a
0.6 0.50.4 0.3
'"•S.JI..II.. LJ
jjg
i
0.20.1 0.0-I 20
40
60
80
100
120
140
Months Fig. 2. Failure-free survival for patients with <1 failed chemotherapy regimen prior to transplantation ( ), those with 2 failed regimens prior to transplantation (••••)> a n d those with > 2 failed regimens prior to transplantation ( ).
Rescue source was significantly associated with overall survival but only marginally associated with failure-free survival in the univariate analyses (Table 2). Patients receiving PSCT had significantly poorer survival than ABMT patients. However, eighty-seven percent of PSCT patients had poor performance status compared to 53 percent of the ABMT patients and ninety-three percent of PSCT patients had failed more than one prior chemotherapy regimen compared to 70 percent of ABMT patients. Because of these confounding conditions in this small group of patients, rescue source was not included in the multivariate analyses. The independent effects of the variables found to be significantly associated with survival and failure-free survival in the univariate analyses were assessed in a
stepwise fashion after first controlling for the number of previous chemotherapy regimens failed (Table 3). When patients were first classified as to whether or not they had failed at most one prior chemotherapy regimen, only performance status was found to be significantly associated with survival (p = 0.013) and failurefree survival (p = 0.035). For patients failing no more than one previous chemotherapy regimen, the estimated four year failure-free survival is 53 percent (95% CI, 29% to 77%) for patients with a good performance status (ECOG 0), and 22 percent (95% CI, 3% to 42%) for patients with poorer performance status (Fig 3). Similarly, when patients were first classified as to whether or not they had failed at most two prior chemotherapy regimens, only performance status was found to be significantly associated with survival (p = 0.012) and failure-free survival (p — 0.045). For patients failing no more than two prior chemotherapy regimens, the estimated four year failure-free survival is 47 percent (95% CI, 31% to 64%) for good performance status patients, and 21 percent (95% CI, 9% to 34%) for poor performance status patients (Fig. 4). Complete remission durability Seven patients who were thought to have achieved only a PR after transplantation were given additional involved-field radiation after the transplant and attained a CR. Nine patients transplanted without clinical evidence of disease survived the transplant and continued in complete remission (CCR). Among the 119 patients transplanted with evidence of active disease, 57 (48%) achieved CR. No significant difference in failure-free survival (p — 0.44) was found for patients in complete remission following transplantation, regardless of how the remission was achieved. Late relapses
Eleven patients relapsed between 24 and 74 months following transplantation. Patients with late relapses were more likely to have fewer extranodal sites of dis-
Table 3. Multivariate models for survival and failure-free survival controlling for previous chemotherapies failed. Risk Ratio" for Failure
Risk Ratio" for Death
Model 1 Previous Chemos. Performance Status 0, 1+ Model 2 Previous Chemos. <2,>2 Performance Status 0,1 +
Estimate
95% CI
p-value
Estimate
95% CI
p-value
2.17
0.99-4.74
0.052
2.22
0.96-5.24
0.068
2.29
1.19-4.41
0.013
2.17
1.06-4.46
0.035
2.07
1.11-3.88
0.022
2.20
1.07-4.52
0.031
2.29
1.20-4.37
0.012
2.08
1.02-4.26
0.045
* Represents the increased risk of either death or failure for the category in bold relative to the unbolded category for each variable.
771 relapse, while five patients with late relapses remain alive between five and 50 months after relapse.
1.0n 0.9
Secondary Malignancies 0.8
I To u.
0.5
0)
0.4
Five patients developed a myelodysplastic syndrome (MDS) following transplantation. The time from transplant to the development of a secondary MDS ranged between 12 and 79 months. Two patients had relapsed following transplantation at the time their MDS was diagnosed, while three were still in remission. All five patients died within one year of development of MDS.
0.3
Pregnancy
o
u
a> a.
0.7 0.6
0.2
"i—:-.-
0.1 0.0-I 20
40
60
80
100
120
140
Months Fig. 3. Failure-free survival for patients with <1 failed chemotherapy regimen and performance status 0 ( ), < 1 failed regimen and performance status 1+ ( • • • • ) , >1 failed regimen and performance status 0 ( ), and >1 failed regimen and performance status l + ( ).
Three women in this series became pregnant. One woman delivered a healthy child from a donated ovum 83 months following transplantation. Another woman, who used ovulatory stimulating agents, became pregnant with twins. She had a spontaneous abortion at 5 1/2 months gestation, 72 months following transplantation. A third woman delivered a healthy child 72 months following transplantation. No ovulatory stimulating agents were utilized.
Discussion 1.0
This report includes patients previously described [8, 9] and extends our preliminary observations on this co0.9 hort of 128 patients [26]. Patients with a good performance status, who had failed at most one chemother0.8 apy regimen prior to transplantation had the best prognosis (Fig. 3). In contrast, the four year failure-free 0.7 survival is estimated as six percent for more heavily treated patients with a poor performance status (Fig. 0.6 4). The negative influence of extensive prior chemo« 0.5 therapy and poor performance status on outcome following ABMT for Hodgkin's disease has previously 0.4 been reported [9,10,14,15]. Nevertheless, these results do not define the optimal 0.3 time for transplantation in Hodgkin's disease since conventional salvage chemotherapy [5-7], and radiation 0.2 therapy [27] may cure some patients. The best results of conventional salvage chemotherapy have been report0.1 ed by the Milan group who noted a freedom from second progression of 51 percent in patients who had 0.0 60 80 40 20 100 120 140 relapsed after an initial remission of at least 12 months [28]. Most reports of conventional salvage chemotherMonths apy are inferior to those reported by the Milan group, Fig. 4. Failure-free survival for patients with < 2 failed chemohowever [5-7]. Analysis from Vancouver suggests that therapy regimens and performance status 0 ( ), <2 failed regimens and performance status 1+ ( • • • • ) , > 2 failed regimens and the outcome of salvage therapy for relapsed Hodgkin's performance status 0 ( ), and >2 failed regimens and perfordisease is dependent on the duration of initial remismance status 1+ ( ). sion, the initial stage of disease, and the presence of systemic symptoms at relapse, rather than on any speease at the time of transplant than those who relapsed cific type of salvage therapy [29]. A decision analysis within the first two years (85% <1 site vs. 53% <1 site, suggests that patients who relapse following MOPP p - 0.028). Six patients with late relapses died of pro- should be treated with conventional salvage chemogressive disease between four and 45 months following therapy first, and that transplantation should be re-
772
served for patients who fail salvage chemotherapy [30]. Factors such as initial remission duration [18, 29], as well as other differences in prognostic variables make it difficult to compare our results with others. The optimal timing of transplantation may only be resolved with prospective trials. Nonetheless, our results in patients who had received only one chemotherapy regimen are better than most results reported for conventional salvage chemotherapy. Since most patients with Hodgkin's disease fail to attain durable remissions with conventional salvage therapy we recommend transplantation following failure of any front-line chemotherapy regimen. Seven patients in this series received post-transplant radiation to areas of apparent residual disease. The remission durability of these patients is similar to that of patients in complete remission at the time of transplantation, and to that of patients who achieved CR with the high dose chemotherapy alone. The use of post-transplant radiotherapy to convert patients into complete remission has been reported by others [12, 16]. The long term outlook for patients following autologous transplantation for Hodgkin's disease is less clear in light of the late relapses we observed. The European Bone Marrow Transplant Group reported a relapse in a patient more than six years following ABMT for Hodgkin's disease [31]. Reece et al. [10] described relapses at 40 and 42 months after ABMT, Phillips et al. [15] described four relapses between 3.3 and 4.5 years following ABMT, and investigators from Royal Marsden Hospital noted a relapse occurring 29 months following ABMT [17]. Patients in this and other reported series are still at risk for relapse. Prolonged follow-up and updated results of previously reported series will help to determine the actual long term outcome of patients following ABMT and PSCT for Hodgkin's disease. Five patients in this series developed myelodysplastic syndromes. Acute myelogenous leukemia and MDS have only been described infrequently following ABMT for Hodgkin's disease [13, 16, 32]. The occurrence of MDS in our patients is most likely related to initial treatment with MOPP chemotherapy [33]. Like other patients with secondary MDS, patients in this series had an extremely poor prognosis. Three patients became pregnant following transplantation. Successful pregnancies have been described following allogeneic bone marrow transplantation [34, 35]. Pregnancy following ABMT has been described less frequently. Premature ovarian failure is common following MOPP chemotherapy [36]. The women who became pregnant in this series had all received MOPP, but all had received this treatment, as well as transplantation, prior to the age of 25. The fact that pregnancy is possible following autologous transplantation with the CBV regimen is valuable with regard to pre-transplant patient counseling. This report demonstrates that long term failure-free
survival is possible following transplantation for Hodgkin's disease. Ultimately, only a relatively small percentage of patients will benefit from transplantation and efforts to improve these results are necessary. Such efforts might include the use of new preparative regimens, dose escalation of existing regimens, tandem transplantation, or adjuvant therapy following transplantation. The use of transplantation may have the biggest impact on outcome in Hodgkin's disease if used as part of the initial therapy. Preliminary data suggest that transplantation used as consolidation therapy for certain patients in first remission may improve results over those of similar patients treated with chemotherapy alone [37].
Acknowledgment
We thank Jene Pierson for assistance in the preparation of this manuscript. Note added in proof
Recently, Chopra et al. (Blood 1993; 81: 1137-45) have reported the development of myelodysplastic syndromes in two patients following ABMT for Hodgkin's disease as well as pregnancy in two patients following ABMT for Hodgkin's disease.
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Correspondence to: Philip J. Bierman, M.D. Assistant Professor of Medicine Section of Hematology/Oncology Department of Internal Medicine University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-3330 U.S.A.