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Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma
original article
Annals of Oncology 19: 1312–1319, 2008 doi:10.1093/annonc/mdn052 Published online 19 March 2008
Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma B. Sirohi, D. Cunningham*, R. Powles, F. Murphy, T. Arkenau, A. Norman, J. Oates, A. Wotherspoon & A. Horwich Lymphoma Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, UK
original article
Background: The purpose of this study was to assess prognostic factors and outcome of patients with relapsed/ refractory Hodgkin’s lymphoma (HL) who received high-dose chemotherapy and autologous stem-cell transplant (ASCT). Patients and methods: Data on 195 patients who received ASCT between 1985 and June 2005 were reviewed. Median time from first treatment to ASCT was 2.6 years (0.4–27.3). Demography at ASCT was 61% stage IV, median age 31 years (18–69), median prior treatment (tx) regimens 3 (2–7), median Hasenclever index 3 (0–6); 150 patients had responding disease [54 complete remission (CR), 96 partial remission (PR)], and 45 patients had untested relapse/refractory disease. Results: Post-ASCT, 61% (119/195) patients attained CR with an overall response (CR + PR) of 85%. Twelve patients had nonrelapse mortality. Of 119 patients attaining CR, 27 relapsed: 3 after attaining CR for >5 years and 1 after attaining CR for >10 years. Median overall survival (OS)/progression-free survival (PFS) from ASCT was 9 years/2.9 years. Five-year OS/PFS was 55% of 44% and 10-year OS/PFS was 49.4% of 37% for whole group. Twenty (10%) patients developed second cancer (seven secondary acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS)). Probability of developing second cancer at 10 years was 14.7% (95% confidence interval 8.9% to 23.8%) and 24.8% at 19 years. Conclusion: These data provide the longest follow-up reported for patients receiving ASCT for relapsed/refractory HL. In addition to previously described prognostic factors, our data show that Hasenclever index <3 influences outcome favorably and attaining CR at ASCT leads to a better outcome. Key words: autotransplantation, hodgkin’s lymphoma, refractory, relapsed
introduction High-dose chemotherapy and autologous bone marrow transplantation was first used in patients with Hodgkin’s lymphoma (HL) almost 45 years ago but it has only in the last two decades become a standard in the treatment pathway for patients with relapsed or refractory disease [1–3]. With the use of peripheral blood stem cells, treatment-related morbidity and mortality are minimal and it offers another potential chance of cure for these patients who have relapsed after multiagent conventional chemotherapy. As prospective randomized studies have proved difficult to accrue to, current recommendations are on the basis of the reports of large series of prospectively collected data [1–3]. Two prospective randomized analyses of HL patients autotransplanted in first relapse show a long-term progressionfree survival (PFS) advantage especially in those who have relapsed after a short first complete remission (CR) [2, 4]. A *Correspondence to: Dr D. Cunningham, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-661-3156; Fax: +44-208-643-9414; E-mail: [email protected]
meta-analyses including >2000 patients confirm this [5]. There was no overall survival (OS) advantage but the studies were not powered to show this. BEAM conditioning with autologous bone marrow rescue was used. Data from single-center series and registry data show that about 40%–50% patients with relapsed HL who have received an autologous stem-cell transplant (ASCT) are alive after 5 years which is encouraging. However, at present there is no refined prognostic information for the individual patient at the time of ASCT that can be used to help them and their physician take an informed decision about the subsequent outcome. The Hasenclever index is a proven guide in designing clinical trials for the treatment of advanced HL and making therapeutic decisions for newly diagnosed patients [6]. However, it has never been used to define outcomes when applied to pivotal moments in the treatment pathway (such as at the time of an ASCT) once treatment has started. The Royal Marsden Hospital series is one of the world’s largest single-center experience of elective single autografts in patients with relapsed/refractory HL patients with the longest follow-up and because of the mature nature of this data in
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Received 25 January 2008; accepted 4 February 2008
original article
Annals of Oncology
terms of PFS and OS, we have used it as a model to see if Hasenclever index can define at the moment of ASCT, subgroups of patients that do better or worse. We have previously reported on 89 such patients; the data on these patients are included in the present paper [7].
patients and methods
eligibility criteria Patients £65 years of age (one patient in this group was >65, considered for ASCT in view of lower biological age and second relapse), left ventricular ejection fraction of >50%, glomerular filtration rate of >40 ml/min, forced expiratory volume in 1 s (FEV1) >50%, or transfer factor >75% predicted on lung function tests (see Table 1). Patients provided informed consent for the therapy.
definitions Patients were staged according to the Ann Arbor system [9]. The prognostic criteria at the time of ASCT were assessed by the Hasenclever index [6] which incorporates seven prognostic factors: serum albumin level <4 g/dl, hemoglobin <10.5 g/dl, male sex, age ‡45 years, stage IV, leukocytosis (‡ 15 · 109/l), and lymphocytopenia (<0.6 · 109/l, <8% of white-cells, or both). Patients were divided into those with 0–2 or ‡3 factors. Status at the time of ASCT was categorized as follows untested relapse—patients who did not receive salvage therapy at relapse and received an ASCT in relapse, chemosensitive—CR were patients with no evidence of disease clinically or radiologically, chemsensitive partial remission (PR) were patients with >50% reduction in size of tumor on computed tomography scan. Patients who did not fit any of these criteria were classified as resistant disease. Response was assessed by the International Union Against Cancer criteria [10]. Patients received well-described regimens of treatment before the ASCT and included ABVD, Stanford V, HYBRID, ChlVPP, VEEP, MOPP/MVPP, LOPP/EVAP, and Hope-Bleo.
treatment plan At relapse, treatment was variable, depending upon prior chemotherapy received (cumulative toxicity of bleomycin, adriamycin). All patients were treated with chemotherapy except six patients with untested relapses at the time of ASCT. Before 1993, patients underwent bone marrow harvest from iliac crests under general anesthesia. From 1993, stem cells were mobilized with 12–16 lg/kg granulocyte colony-stimulating factor and collected by leukapheresis. This was done in those patients with no bone marrow involvement. The stem cells were cryopreserved without further manipulation. For conditioning, melphalan 180–220 mg/m2 was used as a single agent in the first phase of the study. Carmustine (BCNU) 300–600 mg/m2 was then added to melphalan 80–140 mg/m2 as described previously [7]. Thereafter, the regimen MBE was used: melphalan 140 mg/m2, BCNU 300 mg/m2 (Table 1), and etoposide 300 mg/m2. The dose of melphalan was modified on the basis of the creatinine clearance/glomerular filtration rate
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Pulmonary function test (transfer factor)
Previous mantle RT
Dose BCNU
>90% predicted >90% predicted 75–90% predicted <75% predicted <90% predicted
No Yes No No Yes
300 mg/m2 240 mg/m2 240 mg/m2 Nil Nil
a
If previous BCNU has been given, this should be subtracted from the dose calculated according to the above, so that the total dose does not exceed 240 mg or 300 mg/m2. BCNU, Carmustine. (GFR); if 30–50 ml/min: 50% dose reduction, if <30 ml/min: melphalan omitted. The scheduling of drugs was as follows: BCNU day 26 i.v. (over 2 h), etoposide 450 mg/m2 day 25 to day 22 i.v. (over 1 h), melphalan 140 mg/m2 day 21 i.v. ( over 30 min). Cryopreserved marrow or peripheral blood stem cells were returned on day 0. The median total nucleated cells infused were 2.89 · 108 cells/kg.
statistical analysis OS was measured from the date of ASCT to date of death from any cause. PFS was measured from the date of ASCT to time of progression or death from any cause or last follow-up. Nonrelapse mortality was defined as death from any cause other than HL. Survival analysis was carried out according to the Kaplan–Meier method [11]. Multivariate analysis was done using a forward stepwise Cox proportional hazards model. Statistical analyses were computed by means of the SPSS statistical software. Prognostic factors analyzed for both PFS and OS were Hasenclever index at ASCT (0–2 versus ‡3), number of lines of treatment before ASCT (£2 versus >2), time to ASCT (<2 versus ‡2 years), conditioning regimen (MBE versus rest), source of stem cells (marrow versus peripheral blood stem cells (PBSC)), disease status at ASCT (chemosensitive—CR versus chemosensitive PR versus resistant), prior CR ever (yes versus no), response to first-line tx (CR versus PR versus no response), and year of ASCT (upto 1995 versus post-1995).
results patients Table 2 shows patient characteristics at ASCT. These patients were heavily pretreated with median number of lines of treatment being 3 (2–7). In all, 117 (60%) patients received three or more lines of treatment before ASCT. A total of 57% had Hasenclever index ‡3 at ASCT. As shown, seven patients with lymphocyte predominant HL received an ASCT. Table 3 shows the treatment received before ASCT. response and relapse Figure 1 shows the patient flow through treatment received. Post-ASCT, 119 of 195 (61%) patients attained CR, 46 PR, 4 patients had stable disease, 15 patients did not respond and 11 were not assessable for response as all of these patients died of transplant-related mortality (TRM). The overall response rate (CR + PR) was 85%. Of the 119 patients attaining CR, 27 relapsed, 3 of these relapsed at 5, 6, and 7 years post-ASCT, all these patients are alive after further salvage therapy; one patient relapsed after being in CR for 13 years
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Prospectively gathered data on 195 consecutive HL who were autografted from 1985 to June 2005 at the Royal Marsden Hospital were analyzed. Follow-up on patients discharged from the Hospital was undertaken by ringing their general practitioners (GPs). Data on 199 patients were presented at American Society of Clinical Oncology 2005 meeting; on review of case notes, four patients received ASCT as consolidation postfirst-line therapy, hence they were excluded from this analyses [8]. The retrospective study was approved by the Local Regional ethics committee (Trial 2655; NCT00301314).
Table 1. Dosing guidelines for BCNUa
original article
Annals of Oncology
Table 2. Patient characteristics Median age (years) a
Table 3. Summary of therapy received 41 years (range 18–69) 25 (13) 118 (60%) 116 (59%) 4 31 42 118 93
(2%) (16%) (22%) (60%) (48%)
160 21 7 7 3 116 years
(82%)
(range 2–7) (59%) (range 0.4–27.3 years)
122 (62%) 54 96 39 6
(28%) (49%) (20%) (3%)
123 46 26 83 118 131
(63%)
(43%) (60%) (67%)
11.3 59 37 133 5.5 3 0.6 79 68 109 3 111
(range 8.4–15.4) (30%) (range 22–49) (68%) (range 2.3–26.4) (1.1%) (range 0.1–4.3) (40%) (range 36–104) (range 41–213) (range 0–6) (57%)
a
Variables used for Hasenclever index. ASCT, autologous stem-cell transplant; CR, complete remission; GFR, glomerular filtration rate; PR, partial remission; MBE, melphalan, BCNU, etoposide; Hb, hemoglobin.
(nodular sclerosing). Five-year risk of relapse in patients attaining CR was 21%. Overall, progressive disease (PD) was seen in 87 of 195 (45%) patients at 1 months to 12.6 years (median 1.3).
deaths: early and late In all, 93 patients have died—61 died of PD; 12 of TRM; 9 of interstitial pneumonitis related to high dose of BCNU used
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First-line therapy ABVD/Stanford V ChlVPP VEEP MOPP/MVPP LOPP/EVAP Mantle RT/Inv Y RT Other Salvage therapy just before ASCT ABVD ChlVPP VEEP GEM-Pa HYBRID (ChlVPP/EVA) EPIC PmitCEBOM Hope-Bleo BEVAP/EVAP Others No therapy Prior ABVD/Stanford V ever before ASCT Prior bleomycin ever before ASCT Radiotherapy before ASCT Radiotherapy post-ASCT
N = 195 36 55 35 21 23 19/2 4 27 57 35 13 10 11 7 6 10 13 6 91 121 108 29
(47%) (62%) (55%) (15%)
a
With rituximab in three patients with CD20-positive disease. ASCT, autologous stem-cell transplant; Inv Y, inverted Y radiotherapy.
before 1990 (400–600 mg/m2); 1 of renal failure; 1 of multiresistant pseudomonas sepsis; 1 from acute respiratory distress syndrome (combination chemotherapy with methotrexate, vinblastine and cisplatin); 9 died of second cancers (3 leukemia); 5 died as a result of a subsequent stem-cell transplant (4 matched unrelated donor, 1 autologous); 5 died in remission from suicide, progressive multifocal leukoencephalopathy (postmortem on brain biopsy), stroke, cryptococcal meningitis (postmortem), and pericarditis; cause of death remained unknown in 1 patient.
survival A total of 102 patients are alive at median follow-up of 10.3 years (Figure 2). The median OS for the whole group was 9 years [95% confidence interval (CI) 1.9–16 years]. Five-year OS was 55% (95% CI 47.4% and 62.1%) and 10-year OS was 49.4% (95% CI 41% to 57%) for whole group. The median PFS from ASCT was 2.9 years (95% CI 1.1–4.7 years). Five-year PFS was 44% (95% CI 37% to 51%) and 10-year PFS was 37% (95% CI 29.5% to 44%) for the whole group. conditioning The 5-year OS for patients who received conditioning with MBE was 52% compared with 71% with ME and 45% with other regimens (P = 0.14); the 10-year OS being 50%, 57%, and 36% respectively. The 5-year PFS for patients who received conditioning with MBE was 47% compared with 37% with ME and 41% with other regimens (P = 0.4); the 10-year PFS being 40%, 20%, and 36% respectively.
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Age ‡ 45 Malea Ann Arbor stage III–V at presentation Ann Arbor stage at ASCT I II III IVa B symptoms at ASCT Histology Nodular sclerosing Mixed cellularity Lymphocyte depleted Lymphocyte predominant Prior lines of therapy Two or more lines of therapy Median interval from first tx to 2.6 autograft (years) Interval ‡ 2 year Status of remission at ASCT Chemosensitive—CR Chemosensitive—PR Resistant Untested relapses Conditioning MBE ME Others Source of stem cells—peripheral blood Performance status—0 Prior CR ever—yes Blood parameters just before ASCT Median Hb (g/dl) Hb < 10.5 g/dla Median serum albumin (g/l) Serum albumin < 40 g/la Median white cell count (·109/l) White cell count ‡ 15a Median lymphocyte count (·109/l) Lymphocyte count < 0.6a Median serum creatinine (lmol/l) Median creatinine clearance/GFR (ml/min) Median Hasenclever index Hasenclever index ‡ 3
original article
Annals of Oncology
Figure 1. Patient flow through the treatment (CR, complete remission; PR, partial remission; NR, no response; CCR, continued CR; CPR, continued PR; TRM, transplant-related mortality).
chemosensitivity The 5-year OS for patients who were in CR at the time of ASCT was 79% compared with 59% for those in PR and 17% for those with resistant disease at the time of ASCT (P < 0.0001); the 10-year OS being 72%, 54%, and 11%, respectively (Figure 3a and b). The 5-year PFS for patients who were in CR at the time of ASCT was 69% compared with 44% for those in PR and 14% for those with resistant disease at the time of ASCT (P < 0.0001); the 10-year PFS being 59%, 37%, and 7% respectively. Hasenclever index The 5-year OS for patients with a Hasenclever index of zero to two was 71% compared with 41.5% for those with three or more prognostic factors [hazards ratio (HR) 2.29; 95% CI 1.53–3.44; P = 0.0001]; the 10-year OS being 67% and 34%, respectively (Figure 4a and b). The 5-year PFS for patients with a Hasenclever index of zero to two was 60% compared with 32% for those with three or more prognostic factors (HR 1.93; 95% CI 1.38–2.7; P = 0.0001); the 10-year PFS being 53% and 23%, respectively. second malignancies Twenty patients (10%) developed second cancers at a median of 5.8 years (0.2–19 years) post-ASCT. Of these, seven patients developed acute myeloid leukemia or secondary myelodysplastic syndrome (five did not receive prior radiotherapy (RT)); two developed transitional carcinoma of bladder (no prior RT); three basal cell cancer (all had previously received mantle RT); one metastatic gastric cancer (no RT), one metastatic colon cancer (RT pre-ASCT), two metastatic breast cancer (both received mantle RT), one mesothelioma (mantle RT), one diffuse large B-cell lymphoma (received previous RT), one lung cancer (no RT), and one carcinoma of tongue (no RT).
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Figure 2. Overall and progression-free survival.
Probability of developing second cancer at 10 years is 14.7% (95% CI 8.9% to 23.8%) and 24.8% at 19 years. There is no significant difference in probability of developing a solid tumor and secondary AML/MDS (P = 0.17), though the risk of developing a solid tumor increases with longer follow-up. Ten-year probability of developing AML/MDS is 7% compared with 8% for solid tumor; 15-year probability of developing AML/MDS is 7% compared with 19% for solid tumors.
Cox analysis As Table 4 shows, Hasenclever index and chemosensitivity at the time of ASCT are the only two factors predicting both OS and PFS in this group of patients.
discussion The 195 patients in this paper who received an ASCT as treatment for relapsed/refractory HL between 1985 and 2005 represent the longest reported follow-up from a single center and are the basis of determining the risk of late relapse and prognostic criteria relevant to long-term follow-up. In this study, we showed the 10-year OS/PFS of the whole group of 195 patients was 50% of 37% which is comparable to various other published studies as shown in Table 5, [18, 19]. The outcome of this group of patients (5-year and 10-year follow-up data) is better or similar to that reported for a similar group of patients not receiving an autotransplant [20].
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source of stem cells The 5-year OS for patients who received bone marrow as source of stem cells was 51% compared with 62% for those who received peripheral blood stem cells (P = 0.14). The 5-year PFS for patients who received BM was 45% compared with 43% with PBSC (P = 0.11)
original article
Annals of Oncology
The outcome was extremely favorable for the 54 patients who were already in CR at the time of ASCT. These findings have been reported in several recently published trials. The Polish Lymphoma Research Group study identified in their multivariate analysis that CR or PR before ASCT was an independent prognostic factor for the 5-year OS (CR: 77% and PR 71%,
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The results from our study also show that in patients who have had more than two lines of treatment, it is possible to treat patients with multiple recurrences and attain disease control. There was no difference in PFS or OS according to the source of stem cells infused in our study (P = NS). These findings were in accordance with other studies [17, 22]. However, the key to this paper has been our use of the Hasenclever index done at the time of ASCT. This is usually used at diagnosis and has become a standard prognostic test. It has also been used at the time of relapse with some reproducibility but we decided to see if we could use it at the time of ASCT which would of course be at a point when some patients had just completed treatment and were in CR. With measures such as lymphocyte count, this might reflect an effect of treatment rather than disease, but if this staging was going to be useful in the future for determining what the prognosis was for an individual patient, if it could be done just before the ASCT, when the balanced decision was required about the usefulness of such a procedure at that moment in time for that particular patient. We found that the Hasenclever index was a strong indicator of outcome and may be considered at the time of ASCT to predict outcome. Concerning the TRM of this procedure in our patients, the overall mortality for the whole series was 6% but with the
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Figure 3. (A and B) The effect of chemosensitive disease at time of autologous stem-cell transplant on overall and progression-free survival.
original article
Annals of Oncology
Table 4. Multivariate analysis End point
Parameter
Group
OS
Hasenclever index
0–2 ‡3 Chemosensitive—CR Chemosensitive—PR Resistant 0–2 ‡3 Chemosensitive—CR Chemosensitive—PR Resistant
Chemosensitivity
PFS
Hasenclever index Chemosensitivity
Risk ratio
95% CI
P
1.6
1.0–2.6
0.04
1.7 5.08
0.9–3.1 2.7–9.5
0.07 <0.0001
1.6
1.1–2.3
0.01
1.9 3.8
1.2–3.04 2.2–6.5
0.004 <0.0001
OS, overall survival; CI, confidence interval; CR, complete remission; PR, partial remission; PFS, progression-free survival.
optimization of the conditioning regimens (BCNU dose reduction and consideration of previous mantle radiotherapy), the use of PBSCs rather than bone marrow as the source of stem cells, the mortality has declined and currently <1%. This is in accordance with previously reported studies from same time-period. Polish Lymphoma Research
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Group analyzed the outcome of 341 advanced HL patients who underwent ASCT from April 1990 to March 2002 and found a TRM of 5% [17]. Spanish Lymphoma Group reported a TRM of 9% in a group of 494 refractory/relapsed HL patients who underwent a similar approach from January 1984 to May 1998 [21]. A TRM of 13% has been demonstrated
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Figure 4. (A and B) The effect of Hasenclever index at time of autologous stem-cell transplant on overall and progression-free survival.
original article
Annals of Oncology
Table 5. Results of ASCT in relapsed/refractory HL Study/trial
N
Conditioning
OS
PFS/EFS
Current study
195
MBE/ME
Stiff et al. [12] (SWOG) Linch et al. [2] (BNLI) Schmitz et al. [4, 13]; HD-R1 Sureda et al. (EBMT) [14] Tarella et al. (Italian) [15]
81 40 144 357 102
Wadhera. 2006 [16] Czyz et al. (Polish) [17]
127 341
ECy-TBI BEAM BEAM Various regimens High-dose mitoxantrone, L-phenylalanine mustard BuCy E Various regimens
5-year 55%, 10-year 49.4%, 5-year 59% PR, 5-year 17% NR 5-year 54%
5-year 44%, 10-year 37%, 5-year 44% PR, 5-year 14% NR 5-year 41% 3-year 53% (P = 0.025 for ASCT) 3-year 55%, 7-year 49% 5-year 49% 5-year 53%, 5-year 78% CR, 5-year 41% PR, 5-year 7% NR 5-year 48% 5-year 45%, 5-year 62% CS, 5-year 46% resistant
5-year 5-year 5-year 5-year 5-year 5-year 5-year
57% 64%, 5-year 88% CR, 58% PR, 5-year 13% NR 51% 64%, 5-year 79% CS, 77% CR, 5-year 71% PR, 33% for < PR
in a smaller study which analyzed 85 patients with refractory HL who received ASCT in a period from April 1988 to June 1993 [24]. The higher TRM of the latter trial was a result of the use of total body irradiation (TBI) or the use of high-dose BCNU which has been part of the standard conditioning regimens in the earlier days of ASCT. These findings have been confirmed in a smaller Spanish study where TBI was a significant negative prognostic factor for overall TRM (36% versus 9%) [22]. Concerning long-term toxicity, we did not formally assess long-term survivors in this study for quality of life and other toxicity measures but this may be the basis of a later study. However, we did ask GPs to give us from their records information concerning second cancers, the results indicated that even with longer follow-up than other reported studies, the time corrected incidence of cancer is the same as described by others in nontransplant population [25]. Of the seven patients who developed AML (five never received prior RT), three had received prior ChlVPP, two MOPP/MVPP, one Stanford V, one CHOP + procarbazine–bleomycin. As shown by Bonadonna et al. [25], the risk of developing leukemia/MDS is most in the first decade from starting chemotherapy, while the risk for all solid cancers started to increase after the ninth year. Risk of AML was more with MOPP-like regimens (cumulative risk of 6%) and the risk of solid tumors more so with primary ABVD regimens (22% cumulative risk). The two patients with breast carcinoma had both previously received mantle RT which has been shown to be risk factor [26]. Risk is quite likely related to the previous chemotherapy received rather than the ASCT itself as shown by Harrison et al. [27] that there is no evidence of a significantly increased risk of MDS/AML with BEAM and ASCT. Long-term follow-up in this group of patients is a median of 10 years. We are able to define the risk of late relapse. As shown, late relapses were seen even after the patients have been in CR for up to 5 years; one patient relapsed after being in CR for >10 years which is previously not described
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in this disease. This is considered typical of patients with lymphocyte predominant HL [28] but this patient had nodular sclerosing HL. This study provides long-term follow-up evidence of the safety of ASCT in patients with HL and also is sufficiently encouraging in a nonrandomized comparison with published data to suggest that it should be now formally evaluated. This is currently being undertaken in the CORAL and Italian study and it maybe that these studies can test our prognostic criteria using the Hasenclever index to determine whether this is useful in a randomized setting.
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ASCT, autologous stem-cell transplant; HL, Hodgkin’s lymphoma; OS, overall survival; PFS, progression-free survival; MBE, melphalan, BCNU, etoposide; CR, complete remission; PR, partial remission; NR, no response; E, etoposide; Cy, cyclophosphamide; TBI, total body irradiation; B, BCNU; A, cytarabine; M, melphalan; CS, chemosensitive disease; Bu, Busulphan.
original article
Annals of Oncology
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9. Carbone PP, Kaplan HS, Musshoff K et al. Report of the committee on Hodgkin’s disease staging classification. Cancer Res 1971; 31: 1860–1861. 10. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. 11. Kaplan EL, Meier P. Non-parametric estimation from incomplete estimations. J Am Stat Assoc 1958; 53: 457–481. 12. Stiff PJ, Unger JM, Forman SJ et al. The value of augmented preparative regimens combined with an autologous bone marrow transplant for the management of relapsed or refractory Hodgkin disease: a Southwest Oncology Group phase II trial. Biol Blood Marrow Transplant 2003; 9: 529–539. 13. Schmitz N, Haverkamp H, Josting A et al. Long term follow up in relapsed Hodgkin’s disease (HD): updated results of the HD-R1 study comparing conventional chemotherapy (cCT) to high-dose chemotherapy (HDCT) with autologous haemopoetic stem cell transplantation (ASCT) of the German Hodgkin Study Group (GHSG) and the Working Party Lymphoma of the European Group for Blood and Marrow Transplantation (EBMT). J Clin Oncol 2005; 23: 562s(Abstr6508). 14. Sureda A, Constans M, Iriondo A et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol 2005; 16: 625–633. 15. Tarella C, Cuttica A, Vitolo U et al. High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence. Cancer 2003; 97: 2748–2759. 16. Wadehra N, Farag S, Bolwell B et al. Long-term outcome of Hodgkin disease patients following high-dose busulfan, etoposide, cyclophosphamide, and autologous stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 1343–1349. 17. Czyz J, Dziadziuszko R, Knopinska-Postuszuy W et al. Outcome and prognostic factors in advanced Hodgkin’s disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients. Ann Oncol 2004; 15: 1222–1230. 18. Tarella C, Cuttica A, Vitolo U et al. High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano
Annals of Oncology 19: 1312–1319, 2008 doi:10.1093/annonc/mdn052 Published online 19 March 2008
Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma B. Sirohi, D. Cunningham*, R. Powles, F. Murphy, T. Arkenau, A. Norman, J. Oates, A. Wotherspoon & A. Horwich Lymphoma Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, UK
original article
Background: The purpose of this study was to assess prognostic factors and outcome of patients with relapsed/ refractory Hodgkin’s lymphoma (HL) who received high-dose chemotherapy and autologous stem-cell transplant (ASCT). Patients and methods: Data on 195 patients who received ASCT between 1985 and June 2005 were reviewed. Median time from first treatment to ASCT was 2.6 years (0.4–27.3). Demography at ASCT was 61% stage IV, median age 31 years (18–69), median prior treatment (tx) regimens 3 (2–7), median Hasenclever index 3 (0–6); 150 patients had responding disease [54 complete remission (CR), 96 partial remission (PR)], and 45 patients had untested relapse/refractory disease. Results: Post-ASCT, 61% (119/195) patients attained CR with an overall response (CR + PR) of 85%. Twelve patients had nonrelapse mortality. Of 119 patients attaining CR, 27 relapsed: 3 after attaining CR for >5 years and 1 after attaining CR for >10 years. Median overall survival (OS)/progression-free survival (PFS) from ASCT was 9 years/2.9 years. Five-year OS/PFS was 55% of 44% and 10-year OS/PFS was 49.4% of 37% for whole group. Twenty (10%) patients developed second cancer (seven secondary acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS)). Probability of developing second cancer at 10 years was 14.7% (95% confidence interval 8.9% to 23.8%) and 24.8% at 19 years. Conclusion: These data provide the longest follow-up reported for patients receiving ASCT for relapsed/refractory HL. In addition to previously described prognostic factors, our data show that Hasenclever index <3 influences outcome favorably and attaining CR at ASCT leads to a better outcome. Key words: autotransplantation, hodgkin’s lymphoma, refractory, relapsed
introduction High-dose chemotherapy and autologous bone marrow transplantation was first used in patients with Hodgkin’s lymphoma (HL) almost 45 years ago but it has only in the last two decades become a standard in the treatment pathway for patients with relapsed or refractory disease [1–3]. With the use of peripheral blood stem cells, treatment-related morbidity and mortality are minimal and it offers another potential chance of cure for these patients who have relapsed after multiagent conventional chemotherapy. As prospective randomized studies have proved difficult to accrue to, current recommendations are on the basis of the reports of large series of prospectively collected data [1–3]. Two prospective randomized analyses of HL patients autotransplanted in first relapse show a long-term progressionfree survival (PFS) advantage especially in those who have relapsed after a short first complete remission (CR) [2, 4]. A *Correspondence to: Dr D. Cunningham, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-661-3156; Fax: +44-208-643-9414; E-mail: [email protected]
meta-analyses including >2000 patients confirm this [5]. There was no overall survival (OS) advantage but the studies were not powered to show this. BEAM conditioning with autologous bone marrow rescue was used. Data from single-center series and registry data show that about 40%–50% patients with relapsed HL who have received an autologous stem-cell transplant (ASCT) are alive after 5 years which is encouraging. However, at present there is no refined prognostic information for the individual patient at the time of ASCT that can be used to help them and their physician take an informed decision about the subsequent outcome. The Hasenclever index is a proven guide in designing clinical trials for the treatment of advanced HL and making therapeutic decisions for newly diagnosed patients [6]. However, it has never been used to define outcomes when applied to pivotal moments in the treatment pathway (such as at the time of an ASCT) once treatment has started. The Royal Marsden Hospital series is one of the world’s largest single-center experience of elective single autografts in patients with relapsed/refractory HL patients with the longest follow-up and because of the mature nature of this data in
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Received 25 January 2008; accepted 4 February 2008
original article
Annals of Oncology
terms of PFS and OS, we have used it as a model to see if Hasenclever index can define at the moment of ASCT, subgroups of patients that do better or worse. We have previously reported on 89 such patients; the data on these patients are included in the present paper [7].
patients and methods
eligibility criteria Patients £65 years of age (one patient in this group was >65, considered for ASCT in view of lower biological age and second relapse), left ventricular ejection fraction of >50%, glomerular filtration rate of >40 ml/min, forced expiratory volume in 1 s (FEV1) >50%, or transfer factor >75% predicted on lung function tests (see Table 1). Patients provided informed consent for the therapy.
definitions Patients were staged according to the Ann Arbor system [9]. The prognostic criteria at the time of ASCT were assessed by the Hasenclever index [6] which incorporates seven prognostic factors: serum albumin level <4 g/dl, hemoglobin <10.5 g/dl, male sex, age ‡45 years, stage IV, leukocytosis (‡ 15 · 109/l), and lymphocytopenia (<0.6 · 109/l, <8% of white-cells, or both). Patients were divided into those with 0–2 or ‡3 factors. Status at the time of ASCT was categorized as follows untested relapse—patients who did not receive salvage therapy at relapse and received an ASCT in relapse, chemosensitive—CR were patients with no evidence of disease clinically or radiologically, chemsensitive partial remission (PR) were patients with >50% reduction in size of tumor on computed tomography scan. Patients who did not fit any of these criteria were classified as resistant disease. Response was assessed by the International Union Against Cancer criteria [10]. Patients received well-described regimens of treatment before the ASCT and included ABVD, Stanford V, HYBRID, ChlVPP, VEEP, MOPP/MVPP, LOPP/EVAP, and Hope-Bleo.
treatment plan At relapse, treatment was variable, depending upon prior chemotherapy received (cumulative toxicity of bleomycin, adriamycin). All patients were treated with chemotherapy except six patients with untested relapses at the time of ASCT. Before 1993, patients underwent bone marrow harvest from iliac crests under general anesthesia. From 1993, stem cells were mobilized with 12–16 lg/kg granulocyte colony-stimulating factor and collected by leukapheresis. This was done in those patients with no bone marrow involvement. The stem cells were cryopreserved without further manipulation. For conditioning, melphalan 180–220 mg/m2 was used as a single agent in the first phase of the study. Carmustine (BCNU) 300–600 mg/m2 was then added to melphalan 80–140 mg/m2 as described previously [7]. Thereafter, the regimen MBE was used: melphalan 140 mg/m2, BCNU 300 mg/m2 (Table 1), and etoposide 300 mg/m2. The dose of melphalan was modified on the basis of the creatinine clearance/glomerular filtration rate
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Pulmonary function test (transfer factor)
Previous mantle RT
Dose BCNU
>90% predicted >90% predicted 75–90% predicted <75% predicted <90% predicted
No Yes No No Yes
300 mg/m2 240 mg/m2 240 mg/m2 Nil Nil
a
If previous BCNU has been given, this should be subtracted from the dose calculated according to the above, so that the total dose does not exceed 240 mg or 300 mg/m2. BCNU, Carmustine. (GFR); if 30–50 ml/min: 50% dose reduction, if <30 ml/min: melphalan omitted. The scheduling of drugs was as follows: BCNU day 26 i.v. (over 2 h), etoposide 450 mg/m2 day 25 to day 22 i.v. (over 1 h), melphalan 140 mg/m2 day 21 i.v. ( over 30 min). Cryopreserved marrow or peripheral blood stem cells were returned on day 0. The median total nucleated cells infused were 2.89 · 108 cells/kg.
statistical analysis OS was measured from the date of ASCT to date of death from any cause. PFS was measured from the date of ASCT to time of progression or death from any cause or last follow-up. Nonrelapse mortality was defined as death from any cause other than HL. Survival analysis was carried out according to the Kaplan–Meier method [11]. Multivariate analysis was done using a forward stepwise Cox proportional hazards model. Statistical analyses were computed by means of the SPSS statistical software. Prognostic factors analyzed for both PFS and OS were Hasenclever index at ASCT (0–2 versus ‡3), number of lines of treatment before ASCT (£2 versus >2), time to ASCT (<2 versus ‡2 years), conditioning regimen (MBE versus rest), source of stem cells (marrow versus peripheral blood stem cells (PBSC)), disease status at ASCT (chemosensitive—CR versus chemosensitive PR versus resistant), prior CR ever (yes versus no), response to first-line tx (CR versus PR versus no response), and year of ASCT (upto 1995 versus post-1995).
results patients Table 2 shows patient characteristics at ASCT. These patients were heavily pretreated with median number of lines of treatment being 3 (2–7). In all, 117 (60%) patients received three or more lines of treatment before ASCT. A total of 57% had Hasenclever index ‡3 at ASCT. As shown, seven patients with lymphocyte predominant HL received an ASCT. Table 3 shows the treatment received before ASCT. response and relapse Figure 1 shows the patient flow through treatment received. Post-ASCT, 119 of 195 (61%) patients attained CR, 46 PR, 4 patients had stable disease, 15 patients did not respond and 11 were not assessable for response as all of these patients died of transplant-related mortality (TRM). The overall response rate (CR + PR) was 85%. Of the 119 patients attaining CR, 27 relapsed, 3 of these relapsed at 5, 6, and 7 years post-ASCT, all these patients are alive after further salvage therapy; one patient relapsed after being in CR for 13 years
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Prospectively gathered data on 195 consecutive HL who were autografted from 1985 to June 2005 at the Royal Marsden Hospital were analyzed. Follow-up on patients discharged from the Hospital was undertaken by ringing their general practitioners (GPs). Data on 199 patients were presented at American Society of Clinical Oncology 2005 meeting; on review of case notes, four patients received ASCT as consolidation postfirst-line therapy, hence they were excluded from this analyses [8]. The retrospective study was approved by the Local Regional ethics committee (Trial 2655; NCT00301314).
Table 1. Dosing guidelines for BCNUa
original article
Annals of Oncology
Table 2. Patient characteristics Median age (years) a
Table 3. Summary of therapy received 41 years (range 18–69) 25 (13) 118 (60%) 116 (59%) 4 31 42 118 93
(2%) (16%) (22%) (60%) (48%)
160 21 7 7 3 116 years
(82%)
(range 2–7) (59%) (range 0.4–27.3 years)
122 (62%) 54 96 39 6
(28%) (49%) (20%) (3%)
123 46 26 83 118 131
(63%)
(43%) (60%) (67%)
11.3 59 37 133 5.5 3 0.6 79 68 109 3 111
(range 8.4–15.4) (30%) (range 22–49) (68%) (range 2.3–26.4) (1.1%) (range 0.1–4.3) (40%) (range 36–104) (range 41–213) (range 0–6) (57%)
a
Variables used for Hasenclever index. ASCT, autologous stem-cell transplant; CR, complete remission; GFR, glomerular filtration rate; PR, partial remission; MBE, melphalan, BCNU, etoposide; Hb, hemoglobin.
(nodular sclerosing). Five-year risk of relapse in patients attaining CR was 21%. Overall, progressive disease (PD) was seen in 87 of 195 (45%) patients at 1 months to 12.6 years (median 1.3).
deaths: early and late In all, 93 patients have died—61 died of PD; 12 of TRM; 9 of interstitial pneumonitis related to high dose of BCNU used
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First-line therapy ABVD/Stanford V ChlVPP VEEP MOPP/MVPP LOPP/EVAP Mantle RT/Inv Y RT Other Salvage therapy just before ASCT ABVD ChlVPP VEEP GEM-Pa HYBRID (ChlVPP/EVA) EPIC PmitCEBOM Hope-Bleo BEVAP/EVAP Others No therapy Prior ABVD/Stanford V ever before ASCT Prior bleomycin ever before ASCT Radiotherapy before ASCT Radiotherapy post-ASCT
N = 195 36 55 35 21 23 19/2 4 27 57 35 13 10 11 7 6 10 13 6 91 121 108 29
(47%) (62%) (55%) (15%)
a
With rituximab in three patients with CD20-positive disease. ASCT, autologous stem-cell transplant; Inv Y, inverted Y radiotherapy.
before 1990 (400–600 mg/m2); 1 of renal failure; 1 of multiresistant pseudomonas sepsis; 1 from acute respiratory distress syndrome (combination chemotherapy with methotrexate, vinblastine and cisplatin); 9 died of second cancers (3 leukemia); 5 died as a result of a subsequent stem-cell transplant (4 matched unrelated donor, 1 autologous); 5 died in remission from suicide, progressive multifocal leukoencephalopathy (postmortem on brain biopsy), stroke, cryptococcal meningitis (postmortem), and pericarditis; cause of death remained unknown in 1 patient.
survival A total of 102 patients are alive at median follow-up of 10.3 years (Figure 2). The median OS for the whole group was 9 years [95% confidence interval (CI) 1.9–16 years]. Five-year OS was 55% (95% CI 47.4% and 62.1%) and 10-year OS was 49.4% (95% CI 41% to 57%) for whole group. The median PFS from ASCT was 2.9 years (95% CI 1.1–4.7 years). Five-year PFS was 44% (95% CI 37% to 51%) and 10-year PFS was 37% (95% CI 29.5% to 44%) for the whole group. conditioning The 5-year OS for patients who received conditioning with MBE was 52% compared with 71% with ME and 45% with other regimens (P = 0.14); the 10-year OS being 50%, 57%, and 36% respectively. The 5-year PFS for patients who received conditioning with MBE was 47% compared with 37% with ME and 41% with other regimens (P = 0.4); the 10-year PFS being 40%, 20%, and 36% respectively.
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Age ‡ 45 Malea Ann Arbor stage III–V at presentation Ann Arbor stage at ASCT I II III IVa B symptoms at ASCT Histology Nodular sclerosing Mixed cellularity Lymphocyte depleted Lymphocyte predominant Prior lines of therapy Two or more lines of therapy Median interval from first tx to 2.6 autograft (years) Interval ‡ 2 year Status of remission at ASCT Chemosensitive—CR Chemosensitive—PR Resistant Untested relapses Conditioning MBE ME Others Source of stem cells—peripheral blood Performance status—0 Prior CR ever—yes Blood parameters just before ASCT Median Hb (g/dl) Hb < 10.5 g/dla Median serum albumin (g/l) Serum albumin < 40 g/la Median white cell count (·109/l) White cell count ‡ 15a Median lymphocyte count (·109/l) Lymphocyte count < 0.6a Median serum creatinine (lmol/l) Median creatinine clearance/GFR (ml/min) Median Hasenclever index Hasenclever index ‡ 3
original article
Annals of Oncology
Figure 1. Patient flow through the treatment (CR, complete remission; PR, partial remission; NR, no response; CCR, continued CR; CPR, continued PR; TRM, transplant-related mortality).
chemosensitivity The 5-year OS for patients who were in CR at the time of ASCT was 79% compared with 59% for those in PR and 17% for those with resistant disease at the time of ASCT (P < 0.0001); the 10-year OS being 72%, 54%, and 11%, respectively (Figure 3a and b). The 5-year PFS for patients who were in CR at the time of ASCT was 69% compared with 44% for those in PR and 14% for those with resistant disease at the time of ASCT (P < 0.0001); the 10-year PFS being 59%, 37%, and 7% respectively. Hasenclever index The 5-year OS for patients with a Hasenclever index of zero to two was 71% compared with 41.5% for those with three or more prognostic factors [hazards ratio (HR) 2.29; 95% CI 1.53–3.44; P = 0.0001]; the 10-year OS being 67% and 34%, respectively (Figure 4a and b). The 5-year PFS for patients with a Hasenclever index of zero to two was 60% compared with 32% for those with three or more prognostic factors (HR 1.93; 95% CI 1.38–2.7; P = 0.0001); the 10-year PFS being 53% and 23%, respectively. second malignancies Twenty patients (10%) developed second cancers at a median of 5.8 years (0.2–19 years) post-ASCT. Of these, seven patients developed acute myeloid leukemia or secondary myelodysplastic syndrome (five did not receive prior radiotherapy (RT)); two developed transitional carcinoma of bladder (no prior RT); three basal cell cancer (all had previously received mantle RT); one metastatic gastric cancer (no RT), one metastatic colon cancer (RT pre-ASCT), two metastatic breast cancer (both received mantle RT), one mesothelioma (mantle RT), one diffuse large B-cell lymphoma (received previous RT), one lung cancer (no RT), and one carcinoma of tongue (no RT).
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Figure 2. Overall and progression-free survival.
Probability of developing second cancer at 10 years is 14.7% (95% CI 8.9% to 23.8%) and 24.8% at 19 years. There is no significant difference in probability of developing a solid tumor and secondary AML/MDS (P = 0.17), though the risk of developing a solid tumor increases with longer follow-up. Ten-year probability of developing AML/MDS is 7% compared with 8% for solid tumor; 15-year probability of developing AML/MDS is 7% compared with 19% for solid tumors.
Cox analysis As Table 4 shows, Hasenclever index and chemosensitivity at the time of ASCT are the only two factors predicting both OS and PFS in this group of patients.
discussion The 195 patients in this paper who received an ASCT as treatment for relapsed/refractory HL between 1985 and 2005 represent the longest reported follow-up from a single center and are the basis of determining the risk of late relapse and prognostic criteria relevant to long-term follow-up. In this study, we showed the 10-year OS/PFS of the whole group of 195 patients was 50% of 37% which is comparable to various other published studies as shown in Table 5, [18, 19]. The outcome of this group of patients (5-year and 10-year follow-up data) is better or similar to that reported for a similar group of patients not receiving an autotransplant [20].
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source of stem cells The 5-year OS for patients who received bone marrow as source of stem cells was 51% compared with 62% for those who received peripheral blood stem cells (P = 0.14). The 5-year PFS for patients who received BM was 45% compared with 43% with PBSC (P = 0.11)
original article
Annals of Oncology
The outcome was extremely favorable for the 54 patients who were already in CR at the time of ASCT. These findings have been reported in several recently published trials. The Polish Lymphoma Research Group study identified in their multivariate analysis that CR or PR before ASCT was an independent prognostic factor for the 5-year OS (CR: 77% and PR 71%,
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The results from our study also show that in patients who have had more than two lines of treatment, it is possible to treat patients with multiple recurrences and attain disease control. There was no difference in PFS or OS according to the source of stem cells infused in our study (P = NS). These findings were in accordance with other studies [17, 22]. However, the key to this paper has been our use of the Hasenclever index done at the time of ASCT. This is usually used at diagnosis and has become a standard prognostic test. It has also been used at the time of relapse with some reproducibility but we decided to see if we could use it at the time of ASCT which would of course be at a point when some patients had just completed treatment and were in CR. With measures such as lymphocyte count, this might reflect an effect of treatment rather than disease, but if this staging was going to be useful in the future for determining what the prognosis was for an individual patient, if it could be done just before the ASCT, when the balanced decision was required about the usefulness of such a procedure at that moment in time for that particular patient. We found that the Hasenclever index was a strong indicator of outcome and may be considered at the time of ASCT to predict outcome. Concerning the TRM of this procedure in our patients, the overall mortality for the whole series was 6% but with the
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Figure 3. (A and B) The effect of chemosensitive disease at time of autologous stem-cell transplant on overall and progression-free survival.
original article
Annals of Oncology
Table 4. Multivariate analysis End point
Parameter
Group
OS
Hasenclever index
0–2 ‡3 Chemosensitive—CR Chemosensitive—PR Resistant 0–2 ‡3 Chemosensitive—CR Chemosensitive—PR Resistant
Chemosensitivity
PFS
Hasenclever index Chemosensitivity
Risk ratio
95% CI
P
1.6
1.0–2.6
0.04
1.7 5.08
0.9–3.1 2.7–9.5
0.07 <0.0001
1.6
1.1–2.3
0.01
1.9 3.8
1.2–3.04 2.2–6.5
0.004 <0.0001
OS, overall survival; CI, confidence interval; CR, complete remission; PR, partial remission; PFS, progression-free survival.
optimization of the conditioning regimens (BCNU dose reduction and consideration of previous mantle radiotherapy), the use of PBSCs rather than bone marrow as the source of stem cells, the mortality has declined and currently <1%. This is in accordance with previously reported studies from same time-period. Polish Lymphoma Research
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Group analyzed the outcome of 341 advanced HL patients who underwent ASCT from April 1990 to March 2002 and found a TRM of 5% [17]. Spanish Lymphoma Group reported a TRM of 9% in a group of 494 refractory/relapsed HL patients who underwent a similar approach from January 1984 to May 1998 [21]. A TRM of 13% has been demonstrated
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Figure 4. (A and B) The effect of Hasenclever index at time of autologous stem-cell transplant on overall and progression-free survival.
original article
Annals of Oncology
Table 5. Results of ASCT in relapsed/refractory HL Study/trial
N
Conditioning
OS
PFS/EFS
Current study
195
MBE/ME
Stiff et al. [12] (SWOG) Linch et al. [2] (BNLI) Schmitz et al. [4, 13]; HD-R1 Sureda et al. (EBMT) [14] Tarella et al. (Italian) [15]
81 40 144 357 102
Wadhera. 2006 [16] Czyz et al. (Polish) [17]
127 341
ECy-TBI BEAM BEAM Various regimens High-dose mitoxantrone, L-phenylalanine mustard BuCy E Various regimens
5-year 55%, 10-year 49.4%, 5-year 59% PR, 5-year 17% NR 5-year 54%
5-year 44%, 10-year 37%, 5-year 44% PR, 5-year 14% NR 5-year 41% 3-year 53% (P = 0.025 for ASCT) 3-year 55%, 7-year 49% 5-year 49% 5-year 53%, 5-year 78% CR, 5-year 41% PR, 5-year 7% NR 5-year 48% 5-year 45%, 5-year 62% CS, 5-year 46% resistant
5-year 5-year 5-year 5-year 5-year 5-year 5-year
57% 64%, 5-year 88% CR, 58% PR, 5-year 13% NR 51% 64%, 5-year 79% CS, 77% CR, 5-year 71% PR, 33% for < PR
in a smaller study which analyzed 85 patients with refractory HL who received ASCT in a period from April 1988 to June 1993 [24]. The higher TRM of the latter trial was a result of the use of total body irradiation (TBI) or the use of high-dose BCNU which has been part of the standard conditioning regimens in the earlier days of ASCT. These findings have been confirmed in a smaller Spanish study where TBI was a significant negative prognostic factor for overall TRM (36% versus 9%) [22]. Concerning long-term toxicity, we did not formally assess long-term survivors in this study for quality of life and other toxicity measures but this may be the basis of a later study. However, we did ask GPs to give us from their records information concerning second cancers, the results indicated that even with longer follow-up than other reported studies, the time corrected incidence of cancer is the same as described by others in nontransplant population [25]. Of the seven patients who developed AML (five never received prior RT), three had received prior ChlVPP, two MOPP/MVPP, one Stanford V, one CHOP + procarbazine–bleomycin. As shown by Bonadonna et al. [25], the risk of developing leukemia/MDS is most in the first decade from starting chemotherapy, while the risk for all solid cancers started to increase after the ninth year. Risk of AML was more with MOPP-like regimens (cumulative risk of 6%) and the risk of solid tumors more so with primary ABVD regimens (22% cumulative risk). The two patients with breast carcinoma had both previously received mantle RT which has been shown to be risk factor [26]. Risk is quite likely related to the previous chemotherapy received rather than the ASCT itself as shown by Harrison et al. [27] that there is no evidence of a significantly increased risk of MDS/AML with BEAM and ASCT. Long-term follow-up in this group of patients is a median of 10 years. We are able to define the risk of late relapse. As shown, late relapses were seen even after the patients have been in CR for up to 5 years; one patient relapsed after being in CR for >10 years which is previously not described
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in this disease. This is considered typical of patients with lymphocyte predominant HL [28] but this patient had nodular sclerosing HL. This study provides long-term follow-up evidence of the safety of ASCT in patients with HL and also is sufficiently encouraging in a nonrandomized comparison with published data to suggest that it should be now formally evaluated. This is currently being undertaken in the CORAL and Italian study and it maybe that these studies can test our prognostic criteria using the Hasenclever index to determine whether this is useful in a randomized setting.
references 1. Gribben JG, Linch DC, Singer CR et al. Successful treatment of refractory Hodgkin’s disease by high-dose combination chemotherapy and autologous bone marrow transplantation. Blood 1989; 73: 340–344. 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: 1051–1054. 3. 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: 1137–1145. 4. 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: 2065–2071. 5. Strehl J, Mey U, Glasmacher A et al. High-dose chemotherapy followed by autologous stem cell transplantation as first-line therapy in aggressive nonHodgkin’s lymphoma: a meta-analysis. Haematologica 2003; 88: 1304–1315. 6. Hasenclever D, Diehl V, Armitage JO et al. A prognostic score for advanced Hodgkin’s disease. N Engl J Med 1998; 339: 1506–1514. 7. O’Brien ME, Milan S, Cunningham D et al. High-dose chemotherapy and autologous bone marrow transplant in relapsed Hodgkin’s disease—a pragmatic prognostic index. Br J Cancer 1996; 73: 1272–1277. 8. Sirohi B, Cunningham D, Norman A et al. Long-term outcome of high-dose chemotherapy and autologous stem cell transplantation in relapsed/refractory Hodgkin’s disease: a cohort of 199 pts from Royal Marsden Hospital. J Clin Oncol 2006; 24: 452s(Abstr).
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ASCT, autologous stem-cell transplant; HL, Hodgkin’s lymphoma; OS, overall survival; PFS, progression-free survival; MBE, melphalan, BCNU, etoposide; CR, complete remission; PR, partial remission; NR, no response; E, etoposide; Cy, cyclophosphamide; TBI, total body irradiation; B, BCNU; A, cytarabine; M, melphalan; CS, chemosensitive disease; Bu, Busulphan.
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Annals of Oncology
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