Impact of Conditioning Regimen on Outcome of 2-Year Disease-Free Survivors of Autologous Stem Cell Transplantation for Hodgkin Lymphoma

Original Study

Impact of Conditioning Regimen on Outcome of 2-Year Disease-Free Survivors of Autologous Stem Cell Transplantation for Hodgkin Lymphoma Basem M. William, Fausto R. Loberiza, Jr., Victoria Whalen, Philip J. Bierman, R. Gregory Bociek, Julie M. Vose, James O. Armitage Abstract Autologous stem cell transplantation (ASCT) is the standard of care for relapsed Hodgkin lymphoma (HL) yet the long-term outcomes for 2-year survivors after ASCT have not been well described. We report favorable outcomes of 225 patients with relapsed HL who were alive 2 years after ASCT. The type of chemotherapy regimen received before ASCT had an effect on outcomes. Background: Autologous stem cell transplantation is the standard of care for patients with relapsed HL and the longterm outcomes for survivors 2 years after ASCT have not been well described. No prospective trials have compared the effect of different conditioning regimens on outcomes. Patients and Methods: We searched the Nebraska Lymphoma Study Group database to identify patients with HL who received ASCT from 1984 to 2007. Patients were conditioned with either CBV (cyclophosphamide, carmustine, and etoposide) or BEAM (carmustine, etoposide, cytarabine, and melphalan). Results: At a median follow-up of 8 (range, 2-26) years, 225 patients were alive and disease-free 2 years after ASCT. Analysis was limited to these patients. At 5 years, the progression-free survival (PFS) was 92% for BEAM and 73% for CBV (P ¼ .002) and the overall survival (OS) was 95% for BEAM and 87% for CBV (P ¼ .07). At 10 years, the PFS was 79% for BEAM and 59% for CBV (P ¼ .01) and the OS was 84% for BEAM and 66% for CBV (P ¼ .02). Conclusion: Patients with HL who are disease-free and alive 2 years after ASCT have favorable outcomes. We observed lower risk of progression and longer survival associated with use of BEAM vs. CBV. Patients in the BEAM group received a transplant in more recent years so we cannot exclude the possibility that the superior outcomes seen in the BEAM group are because of better supportive care, use of peripheral blood stem cell grafts, or improvements in salvage therapies before transplantation. Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 4, 417-23 ª 2013 Elsevier Inc. All rights reserved. Keywords: BEAM, Carmustine, CBV, Chemosensitivity, Hematopoietic transplantation, High-dose chemotherapy

Introduction High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with relapsed Hodgkin lymphoma (HL) who are medically fit to undergo transplantation.1 Two randomized trials have shown the superiority Presented, in part, at the American Society of Clinical Oncology annual meeting in 2011 Department of Internal Medicine (Division of Oncology/Hematology), University of Nebraska Medical Center, Omaha, NE Submitted: Nov 9, 2012; Revised: Feb 9, 2013; Accepted: Mar 27, 2013; Epub: Jun 15, 2013 Address for correspondence: Basem M. William, MD, MRCP(UK), Division of Hematology and Oncology, University Hospitals Case Medical Center, 11100 Euclid Ave LKS 5079, Cleveland, OH 44106 Fax: 216-201-5451; e-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.03.009

of ASCT over conventional salvage chemotherapy for patients with relapsed HL.2,3 Multiple HDT therapies have been developed over time, and earlier regimens historically commonly employed total body irradiation, however, none of these regimens have ever been compared directly in randomized trials.4,5 Nevertheless, 2 main regimens gained popularity over the years and have remained the 2 most commonly used HDT regimens for ASCT for relapsed/ refractory HL and other types of lymphomas: CBV (cyclophosphamide, carmustine [bis-chloroethylnitrosourea; BCNU], and etoposide), and BEAM (carmustine, etoposide, cytarabine, and melphalan). There have been few reports directly comparing both regimens.6-8 The separation in time and space render direct comparisons between these regimens methodologically limited. Additionally, little is known regarding the comparative toxicity and efficacy of these regimens because no consensus agreement exists between transplant centers on doses and schedules.9-15

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Autologous Transplantation for Hodgkin Lymphoma Patients with HL who are alive and disease-free for 2 years after ASCT have good outcomes with average overall survival (OS) of 77% because most relapses happen in the first 2 years after ASCT.16 In this study, we report our single-institution experience of 225 patients with HL who were alive and disease-free at 2 years after ASCT and we aimed to compare the effect of transplant conditioning regimen (CBV vs. BEAM) on long-term outcomes of these patients.

Patients and Methods We searched the Nebraska Lymphoma Study Group (NLSG) database to identify patients with HL who received ASCT from the years 1984 to 2007. All patients included in the analysis had a centrally-confirmed histologic diagnosis of HL and provided written consent for inclusion in the NLSG database. The study was approved by the University of Nebraska Medical Center (UNMC) institutional review board. All transplants were performed at UNMC and all transplantation patients had a comprehensive evaluation before ASCT to ensure that they had adequate cardiac, pulmonary, renal, and hepatic functions per institution protocol. Bone marrow was harvested in the operating room under general anesthesia and then frozen at a controlled rate in 10% dimethyl sulfoxide (DMSO). In the early 1980s, cells were frozen using a “dump freeze” method in 6% hydroxyethyl starch and 5% DMSO at 135 C then transferred to liquid nitrogen before switching to controlled-rate freezing in 10% DMSO. Peripheral blood stem cells (PBSCs) were collected using apheresis, after growth factor mobilization per institutional protocol, and frozen at a controlled rate with 10% DMSO.17 Most of the transplantations were performed on an inpatient basis and patients received care in private rooms with laminar airflow with some of the more recent transplantations being performed on an outpatient basis. Patients were conditioned with CBV (cyclophosphamide 6000 mg/m2, carmustine 300 mg/m2, and etoposide 600-900 mg/m2) or BEAM (carmustine 300 mg/m2, etoposide 800 mg/m2, cytarabine 800 mg/m2, and melphalan 140 mg/m2). The administration schedule for both regimens is detailed in Table 1. Patients received growth factor support, supportive transfusions, and prophylactic antimicrobial agents per institutional protocol.

Study Definitions

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For disease status at the time of transplantation, a complete response (CR) was defined as the absence of all clinical and radiographic evidence of disease at the time of transplantation after upfront chemotherapy or salvage chemotherapy after first or subsequent relapse(s). Unconfirmed complete response was defined as small residual radiographic abnormalities that were not known to have progressed for 6 months after transplantation and where the attainment of CR was not confirmed using positron emission tomography imaging. A partial response was defined as > 50% reduction of the surface area of all measurable disease in response to salvage chemotherapy given before transplantation. Primary induction failure was defined as disease that did not respond to upfront induction regimens but was subsequently salvaged with second-line regimens confirming chemosensitivity. Some patients received transplantation in first or subsequent relapses without salvage chemotherapy before ASCT.

Clinical Lymphoma, Myeloma & Leukemia August 2013

Table 1 High Dose Regimens Used Regimen

Dosing Schedule

CBV

Cyclophosphamide 1500 mg/m2 on Days 6 to 3 Carmustine (BCNU) 300 mg/m2 on Day 6 Etoposide (VP-16) 100 to 150 mg/m2 b.i.d. (6 doses) on Days 6 to 4

BEAM

Carmustine (BCNU) 300 mg/m2 on Day 6 Etoposide 100 mg/m2 bid (8 doses) on Days 5 to 2 Cytarabine (Ara-C) 100 mg/m2 b.i.d. (8 doses) on Days 5 to 2 Melphalan 140 mg/m2 on Day 1

Abbreviations: BEAM ¼ carmustine, etoposide, cytarabine, and melphalan; b.i.d. ¼ twice per day; CBV ¼ cyclophosphamide, carmustine, and etoposide.

Statistical Analysis For the purpose of this analysis, patients who were conditioned with CBV were compared with patients who were conditioned with BEAM, and analysis was limited to patients who survived at least 2 years after ASCT. The Wilcoxon test was used to compare continuous variables and the c2 statistic was used to compare categorical variables between the 2 groups. Probability of progression was estimated using cumulative incidence to account for competing risk, and progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Comparisons of time to event distributions were made using the log-rank test. Univariate analysis of progression, PFS, and OS were performed with respect to: type of conditioning regimen used (CBV vs. BEAM), age at transplantation, chemosensitivity at transplantation, histologic type, and the presence of extranodal disease. The independent contributions of all factors associated with transplantation outcome were assessed using stepwise Cox proportional hazard regression analysis. The assumption of proportionality was tested before and after model building. A 2-sided test was used in all calculations. All covariates were considered statistically significant at an a of .05. Analyses were performed using SAS software, version 9.1 (SAS Institute).

Results We identified 461 patients who received transplantation during the study period; 330 (72%) patients were conditioned with CBV and 131 (28%) were conditioned with BEAM. At 2 years after ASCT, 225 (49%) were alive and disease-free and our analysis was limited to those patients. Among the 2-year survivors, 144 (64%) were conditioned with CBV and 81 (36%) were conditioned with BEAM. The median age of patients at transplantation was 33 years (range, 8-64 years). The characteristics of the survivors 2 years after ASCT are summarized in Table 2 according to conditioning regimen received. There were significant differences in patient, disease, and transplantation-related characteristics between the BEAM and CBV groups. There were a greater proportion of patients who were in relapse (without previous salvage chemotherapy), had evidence of advanced stage (Ann Arbor stage III/IV), and had elevated lactate dehydrogenase (LDH) levels, and/or extranodal disease at the time of transplantation in the CBV group. All patients who were conditioned with BEAM received rescue with PBSC grafts and only 44% of patients in the CBV group did so, reflecting the change in institutional practice over the years. There was a greater proportion of patients in whom the interval from diagnosis

Basem M. William et al Table 2 Patient Characteristics Variables (n) Age, Median (Range), years

BEAM (n [ 81) 34 (14-62)

CBV (n [ 144) 32 (8-62)

Age Group, n (%)

P .16 .02

40 and Younger

51 (63)

111 (77)

Older than 40

30 (37)

33 (23)

Male Sex (%)

49 (60)

90 (62)

.77

Caucasian (%)

75 (92)

134 (93)

.90

47 (58)

102 (71)

Not otherwise specified

16 (20)

12 (8)

Lymphocyte predominant

11 (14)

10 (7)

Mixed

5 (6)

15 (10)

Lymphocyte depleted

2 (2)

5 (3)

4 (4)

1 (1)

Type of HL, n (%) Nodular sclerosing

.03

<.001

Disease Status at Transplant, n (%) First CR Second or subsequent CR

21(26)

14 (10)

First relapse

31 (38)

73 (51)

Primary induction failure

18 (22)

16 (11)

7 (9)

40 (28)

CR and unconfirmed CR

21 (26)

19 (13)

I or II

20 (25)

68 (47)

4 (5)

48 (33)

Second or subsequent relapse

<.001

Ann Arbor Staging at Transplant, n (%)

III or IV Missing data

36 (44)

9 (6)

Abnormal Lactate Dehydrogenase Levels at Transplant, n (%)

15 (18)

42 (29)

Presence of B Symptoms, n (%)

22 (27)

30 (21)

Sensitive

50 (62)

91 (63)

Resistant

5 (6)

24 (17)

e

20 (14)

26 (32)

9 (6)

Missing

<.001

Extranodal Involvement at Transplant, n (%) No

49 (60)

93 (64)

Yes

7 (9)

35 (24)

Missing data Interval From Diagnosis to Transplant ‡1 years, n (%)

25 (31)

16 (11)

63 (78)

132 (59)

Peripheral blood stem cells

.003 <.001

Graft Type, n (%) Bone marrow

<.001 <.001

Chemosensitivity at Transplant, n (%)

Untreated

.04

e 81 (100)

80 (56) 64 (44)

Abbreviations: BEAM ¼ carmustine, etoposide, cytarabine, and melphalan; B symptoms ¼ fever, weight loss, and drenching night sweats; CBV ¼ cyclophosphamide, carmustine, and etoposide; CR ¼ complete remission; HL ¼ hodgkin lymphoma.

to transplant was  1 year in the BEAM group compared with the CBV group, and there was a greater proportion of patients who underwent transplantation while having chemoresistant disease in the CBV group.

Outcomes With a median follow-up duration of 8 years for surviving patients (range, 2-26 years), the estimated 5-year PFS probability was 92% for the BEAM and 73% for the CBV group (P ¼ .002). Results of univariate analysis of probabilities of PFS and OS based

on the conditioning regimen received are summarized in Table 3. The estimated 5-year OS probability was 95% for the BEAM and 87% for the CBV group (P ¼ .07). The estimated 10-year PFS probability was 79% for the BEAM and 59% for the CBV group (P ¼ .01). The estimated 10-year OS probability was 84% for the BEAM and 66% for the CBV group (P ¼ .02). The estimated 10-year probability of progression was 4% for the BEAM and 24% for the CBV group (P < .01). The estimated 10-year probability of progression was 9% for the BEAM and 33% for the CBV group (P < .001). The Kaplan-Meier curves for both groups are shown in

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Autologous Transplantation for Hodgkin Lymphoma Table 3 Univariate Outcomes of 2-Year Survivors of Autologous Stem Cell Transplantation for Hodgkin Lymphoma Based on Conditioning Regimen (Probability ± 95% CI) BEAM

CBV

Log-Rank P

PFS

92 (82-96)

73 (65-80)

.002

Overall Survival

95 (84-98)

87 (80-92)

.07

5-Year (Probabilities)a

Figure 1 Kaplan-Meier Curves in the Cohort of Survivors 2 Years After Transplantation (n [ 225) Comparing Outcomes for Patients Conditioned With BEAM (n [ 81) vs. CBV (n [ 144) (A) Progression Free Survival (PFS); (B) Overall Survival (OS); (C) Cumulative Incidence of Progression

A 1.0

10-Year (Probabilities)b

BEAM (n=81)

PFS

79 (61-89)

59 (50-67)

.01

Overall Survival

84 (66-93)

66 (59-73)

.02

Abbreviations: BEAM ¼ carmustine, etoposide, cytarabine, and melphalan; CBV ¼ cyclophosphamide, carmustine, and etoposide; PFS ¼ progression-free survival. a Estimates reflect 3 years after being alive and disease-free for 2 years after transplantation. b Estimates reflect 8 years after being alive and disease-free for 2 years after transplantation.

PFS probability

0.8 CBV (n=144)

0.6 0.4 0.2 Log-rank p-value = 0.004 0.0

Causes of Death There were 62 deaths reported in the CBV group and more than half of these (52%) were secondary to disease progression. There were 6 deaths reported in the BEAM group and only 17% were because of documented disease progression. Also, 6 (4%) died in the CBV group and none in the BEAM group secondary to late organ failures. Deaths from secondary malignancies were reported in 14 (10%) of patients in the CBV vs. 4 (5%) in the BEAM group. Most of the deaths in the BEAM group were because of secondary malignancies (67%) vs. 22% for the CBV group (P ¼ .04; Fisher exact test).

0

5

10

15

20

Years

Survival probability

B 1.0

BEAM (n=81)

0.8 CBV (n=144)

0.6 0.4 0.2 Log-rank p-value = 0.002 0.0 0

5

10

15

20

Years

C 1.0 Log-rank p-value = <0.001 Cumulative incidence

Figure 1. Results of multivariate analyses of probabilities of PFS and OS are summarized in Table 4. Higher relative risk (RR) of progression (4.54; P < .001), treatment failure (2.92; P ¼ .002), and mortality (2.74; P ¼ .03) was observed with the use of CBV compared with BEAM. Higher RR of mortality was also observed with age 40 years or older at time of transplantation (1.69; P ¼ .04) and among those with chemoresistant disease (1.99; P ¼ .02). On multivariate analysis, only the type of conditioning regimen (BEAM vs. CBV), age group (40 years or older), and chemosensitivity predicted outcomes after transplant. Treatment-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were reported in 6 (4%) patients in the CBV group vs. 5 (6%) in the BEAM group (P ¼ .22; Fisher exact test).

0.8 0.6 CBV (n=144)

0.4 0.2

BEAM (n=81)

0.0 0

5

10

15

20

Years

Discussion

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High-dose chemotherapy combined with ASCT is the current standard of care for patients with relapsed HL after salvage chemotherapy, however, the optimal HDT remains unknown. Although CBV and BEAM have never been compared head-to-head in a prospective trial, historic PFS and OS after ASCT using either regimen have generally been comparable. Overall survival at 5 years seems comparable at 44% to 53% for CBV patients and 41% to 55% for BEAM patients.18-22 PFS ranges from 38% to 45% for the CBV group and from 35% to 69% for the BEAM group in various studies.12,18-20,22-24 Many institutions throughout the years, including UNMC, have slowly moved from a CBV to a BEAM regimen based on beliefs that toxicity is reduced using BEAM compared with CBV. A major part of the concern about higher toxicity with CBV is the higher dose of carmustine in which the

Clinical Lymphoma, Myeloma & Leukemia August 2013

Abbreviations: BEAM ¼ carmustine, etoposide, cytarabine, and melphalan; CBV ¼ cyclophosphamide, carmustine, and etoposide.

average dose used by most institutions is 600 mg/m2 or higher, which has been clearly associated with increased pulmonary toxicity, mucositis, and infectious complications in a dose-dependent fashion.12,18,24-27 Wang et al retrospectively compared the outcomes of 72 patients treated with either BEAM or CBV at the University of California San Diego. They showed a statistically significant improved OS with the use of BEAM (84%) vs. CBV (60%) with higher incidence of disease progression in the CBV group. The carmustine dose used was 600 mg/m2 which resulted in more frequent organ toxicities

Basem M. William et al Table 4 Multivariate Analysis of Progression-Free and Overall Survival of Survivors 2 Years After Autologous Stem Cell Transplants for Hodgkin Lymphoma Variable

n

Relative Risk of Treatment Failure (95% CI)

P

Conditioning Regimen BEAM CBV

81 144

1.00 2.92 (1.48-5.75)

.002

Age at Transplant 40 years and younger Older than 40 years

162 62

1.00 2.06 (1.31-3.24)

.002

Relative Risk of Mortality (95% CI) Conditioning Regimen BEAM CBV

81 144

1.00 2.74 (1.13-6.64)

.03

Age at Transplant 40 years and younger Older than 40 years

162 62

1.00 1.69 (1.03-2.78)

.04

Chemosensitivity at Transplant Sensitive

141

Resistant

29

1.99 (1.10-3.57)

1.00 .02

Untreated

20

1.26 (0.60-2.63)

.54

Missing data

35

1.13 (0.43-2.96)

.80

Abbreviations: BEAM ¼ carmustine, etoposide, cytarabine, and melphalan; CBV ¼ cyclophosphamide, carmustine, and etoposide.

(especially pulmonary and hepatic) yet the numbers were small to show differences between regimens.8 Puig et al also retrospectively compared the outcomes of 113 patients with lymphoid malignancies (HL and non-HLs) treated with either CBV or BEAM at the University Hospital La Fe (in Spain). They observed statistically significant higher transplantation-related mortality (TRM) in CBV (25%) vs. BEAM (7%). They also observed an excess of sinusoidal obstruction syndrome in the CBV (11%) vs. the BEAM group (0%). They used a carmustine dose of 800 mg/m2 which is the likely explanation for the higher TRM they observed.7 Our results confirmed the superiority of BEAM over CBV but this superiority is unlikely secondary to lower TRM because we limited our analysis to 2 years after ASCT which did not factor in early mortalities because of HDT regimen. We observed 4% deaths in the CBV group because of delayed end-organ damage occurring at least 2 years after ASCT although we have never used total carmustine doses higher than 300 mg/m2. Many of the patients in this analysis had received consolidative irradiation to the mediastinum after primary therapy which, along with concomitant use of cyclophosphamide might have contributed to higher pulmonary toxicity with the CBV regimen. We believe that a major part of the superior PFS/OS we observed with BEAM is because of lower cumulative incidence of progression beyond 2 years after ASCT. Our results suggest that late relapses do occur and contribute to the lower average OS of long-term survivors of ASCT when compared with population-matched controls.16 The question remains if the difference between groups can be explained by superior efficacy and reduced toxicity of BEAM compared with CBV. We cannot exclude other factors that might have biased our results. First, we have used CBV in our earlier year and slowly switched to BEAM over the past decade so we cannot exclude benefits related to improvement in

supportive care and higher cumulative institutional experience. Second, all of the BEAM recipients exclusively received PBSC support and only 56% of patients receiving CBV-based transplantations did. The use of PBSC support with ASCT was shown to shorten the duration of myelosuppression and might decrease the mortality related to infection and bleeding, and transfusion-related complications.28 Additionally, PBSC grafts were shown to have a higher T/NK cell content and a faster reconstitution of T/NK cells after transplantation, compared with bone marrow grafts, which might mediate an autologous graft vs. lymphoma effect.29,30 Third, the patient selection process has changed over the years: in the earlier years patients in relapse were given a transplantation without pretreating with salvage chemotherapy and hence there were more patients with reported advanced stage, higher LDH, extranodal disease, and chemoresistance in the CBV group. We have shown earlier that patients with relapsed HL who proceeded to ASCT fared better if they did not receive salvage chemotherapy before HDT.31 Other investigators have also shown that relapsed chemosensitive HL patients have similar outcomes if they proceed to HDT/ASCT whether they receive salvage chemotherapy or not.32 Comparing data from different reports about the effect of untreated relapsed disease on outcomes after HDT/ASCT is difficult because of the different rates of refractory disease in such untreated patients. It is possible that the patients in the BEAM group had better outcomes, and less ongoing relapse rates, because of a higher rate of pretreatment with salvage chemotherapy in the relapsed setting in the earlier years, and the switch from cisplatin to the more recent ifosfamide-based salvage regimens which carry less morbidity and mortality. Improvement in supportive care and utilization of PBSC are more likely to affect early TRM, and presence of measurable disease before HDT is more likely to predict disease

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Autologous Transplantation for Hodgkin Lymphoma progression in the first 2 years after ASCT. We believe that limiting the analysis to 2 years after ASCT survivors renders the contributions of these factors on the outcomes of HDT/ASCT less important. We observed almost a twice-higher risk of death with chemoresistance at the time of transplantation which is similar to what was reported by other investigators.33-37 However, chemosensitivity is usually dependent on the intensity of treatment and patients in the CBV group received only 300 mg/m2 of carmustine. This difference would make comparing our results with those of other investigators who used carmustine doses of 600 mg/m2 or higher difficult. Also, at least 38 (17%) patients in our cohort had stage III/IV, 33 (15%) had extranodal disease, and 104/225 (40%) did not receive salvage chemotherapy before proceeding to HDT/ASCT, denoting that a significant proportion of our patients had a significant disease bulk before receiving HDT which might render responses to HDT inferior. Again, refractory disease usually has a dismal outcome and is likely to progress during the first 2 years after ASCT.32,36,38 The presence of chemoresistant disease retained significance in multivariate analysis indicating that it is likely a true predictor of inferior outcome regardless of the type of HDT received, among other factors. An interval of 1 year or longer from diagnosis to transplant was observed in the BEAM vs. the CBV group which is likely a reflection of a more recent era in which the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen has replaced the older MOPP (mustard, vincristine, procarbazine, prednisone), or MOPP alternating with ABVD regimens as the new standard of care for upfront therapy in HL, because of higher CR and failure-free survival rate with ABVD demonstrated by the seminal Cancer and Leukemia group B (CALGB) trial 2 decades ago.39 We observed an excess of mortality from secondary malignancies in the BEAM group which is likely because of less progression of HL after ASCT, improved OS, less death from other causes (including long-term end organ toxicities), and more refined diagnostic methods. We cannot exclude the possibility that BEAM is more procarcinogenic; compared with CBV. We, however, have observed equal rates of MDS and secondary AML in both groups.

Conclusion Patients with HL who are alive and disease-free at 2 years after HDT/ASCT have good outcomes. Patients whose disease was chemoresistant had the worst outcomes after ASCT, which is consistent with what has been previously shown by other investigators.32-38,40 Within the constraints of retrospective study design, we conclude that the use of BEAM conditioning is associated with improved PFS, OS, and lower total cumulative incidence of progression in preference to CBV; within the dose and schedule we used. Our results were consistent with the other 2 singleinstitution retrospective reports comparing BEAM and CBV despite that they used different doses and schedules.7,8

Clinical Practice Points  Autologous stem cell transplantation is the standard of care for

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patients with relapsed HL and the long-term outcomes for 2-year survivors after ASCT have not been well described.  No prospective trials have compared the effect of different highdose regimens (HDT) on outcomes.

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 We retrospectively report the outcomes of 225 patients with









relapsed HL who were alive and disease-free 2 years after ASCT from the NLSG database. The outcomes of these patients were favorable with estimated OS in excess of 65% at 10 years. We observed significantly better OS with the use of BEAM HDT of 84% compared with 66% with the use CBV. Only the type of HDT (BEAM vs. CBV), age group (40 years or older), and chemosensitivity independently predicted outcomes after transplantation. Other investigators have retrospectively reported inferior outcomes with the use of CBV, compared with BEAM, which they ascribed to higher TRM, related to carmustine doses in excess of 600 mg/m2. Our results confirmed the superiority of BEAM over CBV but this is unlikely secondary to lower TRM because we only used a carmustine dose of 300 mg/m2 and limited our analysis to 2 years after ASCT which did not account for early mortalities because of the HDT. In the dose and regimen we used, and acknowledging the limitations of the retrospective design, we observed better outcomes with the use of BEAM, compared with CBV, in patients with relapsed HL undergoing ASCT.

Disclosure Julie M. Vose: Research grant support from Millennium, Allos Therapeutics, Astellas, Bristol-Myers Squibb, Celgene, Genentech, Genzyme, GlaxoSmithKline, Novartis, Pharmacyclics, and Rigel; James O. Armitage: Consultant for Ziopharm, Seattle Genetics, Allos Therapeutics, Eisai, and Biogen Idec. The remaining authors have no conflicts of interest.

References 1. Quddus F, Armitage JO. Salvage therapy for Hodgkin’s lymphoma. Cancer J 2009; 15:161-3. 2. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 1993; 341:1051-4. 3. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet 2002; 359:2065-71. 4. Bierman PJ, Armitage JO. Role of autotransplantation in Hodgkin’s disease. Hematol Oncol Clin North Am 1993; 7:591-611. 5. Goldstone AH, McMillan AK. The place of high-dose therapy with haemopoietic stem cell transplantation in relapsed and refractory Hodgkin’s disease. Ann Oncol 1993; 4(suppl 1):21-7. 6. Fielding AK, Philip T, Carella A, et al. Autologous bone marrow transplantation for lymphoma: a 15-year European bone marrow transplant registry (EBMT) experience of 3325 patients. ASH Annual Meeting Abstracts 1994; 84:169. 7. Puig N, de la Rubia J, Remigia MJ, et al. Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation. Leuk Lymphoma 2006; 47:1488-94. 8. Wang EH, Chen YA, Corringham S, et al. High-dose CEB vs BEAM with autologous stem cell transplant in lymphoma. Bone Marrow Transplant 2004; 34: 581-7. 9. Arranz R, Tomas JF, Gil-Fernandez JJ, et al. Autologous stem cell transplantation (ASCT) for poor prognostic Hodgkin’s disease (HD): comparative results with two CBV regimens and importance of disease status at transplant. Bone Marrow Transplant 1998; 21:779-86. 10. Carella AM, Congiu AM, Gaozza E, et al. High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin’s disease patients: an Italian study group report. J Clin Oncol 1988; 6:1411-6. 11. Horning SJ, Chao NJ, Negrin RS, et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood 1997; 89:801-13.

Basem M. William et al 12. Patti C, Majolino I, Scime R, et al. High-dose cyclophosphamide, etoposide and BCNU (CVB) with autologous stem cell rescue in malignant lymphomas. Eur J Haematol 1993; 51:18-24. 13. Reece DE, Barnett MJ, Shepherd JD, et al. High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV þ/- P) and autologous transplantation for patients with Hodgkin’s disease who fail to enter a complete remission after combination chemotherapy. Blood 1995; 86:451-6. 14. Sureda A, Arranz R, Iriondo A, et al. Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group. J Clin Oncol 2001; 19:1395-404. 15. Wheeler C, Eickhoff C, Elias A, et al. High-dose cyclophosphamide, carmustine, and etoposide with autologous transplantation in Hodgkin’s disease: a prognostic model for treatment outcomes. Biol Blood Marrow Transplant 1997; 3:98-106. 16. Majhail NS, Bajorunaite R, Lazarus HM, et al. Long-term survival and late relapse in 2-year survivors of autologous haematopoietic cell transplantation for Hodgkin and non-Hodgkin lymphoma. Br J Haematol 2009; 147:129-39. 17. Kessinger A, Bierman PJ, Vose JM, et al. High-dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin’s disease. Blood 1991; 77:2322-5. 18. Reece DE, Barnett MJ, Connors JM, et al. Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol 1991; 9:1871-9. 19. Bierman PJ, Anderson JR, Freeman MB, et al. High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin’s disease patients following first relapse after chemotherapy. Ann Oncol 1996; 7:151-6. 20. Chopra R, Wotherspoon AC, Blair S, et al. Detection and significance of bone marrow infiltration at the time of autologous bone marrow transplantation in Hodgkin’s disease. Br J Haematol 1994; 87:647-9. 21. Fleming DR, Wolff SN, Fay JW, et al. Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin’s disease: a phase II study from the North American Marrow Transplant Group. Leuk Lymphoma 1999; 35:91-8. 22. Mills W, Chopra R, McMillan A, et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13:588-95. 23. Argiris A, Seropian S, Cooper DL. High-dose BEAM chemotherapy with autologous peripheral blood progenitor-cell transplantation for unselected patients with primary refractory or relapsed Hodgkin’s disease. Ann Oncol 2000; 11:665-72. 24. Reece DE, Nevill TJ, Sayegh A, et al. Regimen-related toxicity and non-relapse mortality with high-dose cyclophosphamide, carmustine (BCNU) and etoposide (VP16-213) (CBV) and CBV plus cisplatin (CBVP) followed by autologous stem cell transplantation in patients with Hodgkin’s disease. Bone Marrow Transplant 1999; 23:1131-8. 25. Alessandrino EP, Bernasconi P, Colombo A, et al. Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor

26. 27.

28. 29.

30. 31. 32. 33. 34. 35.

36. 37. 38. 39. 40.

cell transplantation in hematological malignancies. Bone Marrow Transplant 2000; 25:309-13. Schmitz N, Glass B, Dreger P, et al. High-dose chemotherapy and hematopoietic stem cell rescue in patients with relapsed Hodgkin’s disease. Ann Hematol 1993; 66:251-6. Wheeler C, Antin JH, Churchill WH, et al. Cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation in refractory Hodgkin’s disease and non-Hodgkin’s lymphoma: a dose-finding study. J Clin Oncol 1990; 8: 648-56. Vose JM, Sharp G, Chan WC, et al. Autologous transplantation for aggressive non-Hodgkin’s lymphoma: results of a randomized trial evaluating graft source and minimal residual disease. J Clin Oncol 2002; 20:2344-52. Hassan HT, Stockschlader M, Schleimer B, et al. Comparison of the content and subpopulations of CD3 and CD34 positive cells in bone marrow harvests and G-CSF-mobilized peripheral blood leukapheresis products from healthy adult donors. Transpl Immunol 1996; 4:319-23. Rosillo MC, Ortuno F, Moraleda JM, et al. Immune recovery after autologous or rhG-CSF primed PBSC transplantation. Eur J Haematol 1996; 56:301-7. Bierman PJ, Bagin RG, Jagannath S, et al. High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin’s disease: long-term follow-up in 128 patients. Ann Oncol 1993; 4:767-73. Martinez C, Salamero O, Arenillas L, et al. Autologous stem cell transplantation for patients with active Hodgkin’s lymphoma: long-term outcome of 61 patients from a single institution. Leuk Lymphoma 2007; 48:1968-75. Chopra R, McMillan AK, Linch DC, et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin’s disease. A single-center eight-year study of 155 patients. Blood 1993; 81:1137-45. Crump M, Smith AM, Brandwein J, et al. High-dose etoposide and melphalan, and autologous bone marrow transplantation for patients with advanced Hodgkin’s disease: importance of disease status at transplant. J Clin Oncol 1993; 11:704-11. Josting A, Katay I, Rueffer U, et al. Favorable outcome of patients with relapsed or refractory Hodgkin’s disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (DexBEAM). Ann Oncol 1998; 9:289-95. Josting A, Rueffer U, Franklin J, et al. Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood 2000; 96:1280-6. Rapoport AP, Rowe JM, Kouides PA, et al. One hundred autotransplants for relapsed or refractory Hodgkin’s disease and lymphoma: value of pretransplant disease status for predicting outcome. J Clin Oncol 1993; 11:2351-61. Lazarus HM, Rowlings PA, Zhang MJ, et al. Autotransplants for Hodgkin’s disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 1999; 17:534-45. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992; 327:1478-84. Reece DE, Connors JM, Spinelli JJ, et al. Intensive therapy with cyclophosphamide, carmustine, etoposide þ/- cisplatin, and autologous bone marrow transplantation for Hodgkin’s disease in first relapse after combination chemotherapy. Blood 1994; 83:1193-9.

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