Albert Ludwigs University Medical Center, Department of Hematology and Oncology, Freiburg, Germany
* Correspondence to: Dr J. Finke, Albert Ludwigs University Medical Center, Department of Hematology and Oncology, Hugstetter Str. 55, D-79106 Freiburg, Germany. Tel: +49-761-270-3408; Fax: +49-761-270-3658; Email: finke{at}mm11.ukl.uni-freiburg.de
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Abstract |
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Patients and methods: Eligible patients were 33 consecutive hg B-NHL patients responding to first-line chemotherapy and fulfilling at least one of the following criteria: stage III or IV, bulky disease, elevated lactate dehydrogenase or failure to achieve complete remission (CR). Twenty-two of 33 patients (67%) had two or three risk factors with respect to the aaIPI. All patients received HDCT with ASCT after a minimum of 6 weeks of VACOP-B standard therapy and VIP-E for mobilization.
Results: After ASCT, 31 patients (94%) achieved CR. No treatment-related death occurred. The cumulative incidence of relapse at a medium follow-up of 10 years is 16% for 31 of 33 patients achieving CR. Twenty-five of 33 patients are in sustained CR with a disease-free survival of 76% [95% confidence interval (CI) 67% to 86%]. The overall survival at a median follow-up of 122 months (range 86148) is 79% (95% CI 68% to 89%).
Conclusions: The results suggest that up-front HDCT with ASCT may improve long-term outcome in high-risk patients with chemotherapy-sensitive hg B-NHL when compared to historic populations treated solely with dose-intense chemotherapy. We observed that long-term survival of high-risk (two to three risk factors) patients is comparable to low-risk (zero to one risk factor) patients after HDCT and ASCT with a low incidence of late relapse.
Key words: age-adjusted international prognostic index (aaIPI), autologous stem-cell transplantation (ASCT), chemosensitive disease, high-grade B-cell non-Hodgkin's lymphoma (hg B-NHL), high-dose chemotherapy (HDCT), long-term follow-up
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Introduction |
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We here report long-term follow-up results with HDCT and ASCT in 33 consecutive patients treated for hg B-NHL, with chemosensitive disease after first-line standard chemotherapy. We analyzed the outcome of all patients as well as subgroups according to the aaIPI score principally to address two issues: first, to evaluate the long-term benefit from HDCT with ASCT as part of the initial treatment for patients with chemosensitive hg B-NHL; and secondly, to detect significant PFS and OS differences after ASCT between high- and low-risk constellations according to aaIPI in the long-term follow-up.
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Patients and methods |
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Statistical analysis
Analyses were performed to estimate OS and disease-free survival (DFS), employing the KaplanMeier method [26]. Survival was calculated from initial diagnosis until the patients' death (OS), or relapse or patients death (DFS). To compare the survival distributions with respect to the aaIPI, the log-rank test was applied at a 95% confidence interval (CI), resulting in a P-value and a standard error [27
]. All statistical analysis was performed using SPSS version 11.0® and GraphPad Prism3® software. In order to exclude a significantly different distribution of clinical characteristics other than the aaIPI criteria, the low-risk (IPI 0/1) and high-risk (IPI 2/3) groups were compared in a multivariate analysis. Clinical characteristics that are predictors of DFS and OS, including age, gender, histological subtype, bulky disease, renal, hepatic and cardiac function were investigated. Statistical significance was defined as P<0.05.
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Results |
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Nine patients received radiotherapy for consolidation. Two patients never achieving CR died due to the underlying disease 5 and 6 months after ASCT, respectively. Up to 31 December 2003, five of 31 patients relapsed at 1, 6, 31, 55 and 127 months after ASCT. The first two of these patients finally died due to progressive disease. The third patient received salvage therapy and a MUD transplantation in partial remission. She died in CR on day +106 due to respiratory failure with interstitial pneumonia. The fourth patient relapsed at a site of former extranodal bulk and received a second ASCT, but progressed again 3 months later. The patient relapsing 127 months after ASCT received salvage therapy with prednisolone and cyclophosphamide. One patient died 95 months after transplant in CR due to pulmonary embolism and another patient developed a lung cancer 83 months after transplantation and is still alive. The lung cancer was diagnosed incidentally by chest X-rays and was a pT1N0M0 stage tumor according to the UICC classification. After resection of the upper lobe of the right lung, the patient is currently in sustained remission, 7 years after diagnosis of the lung cancer. The patient was a non-smoker and had no environmental predisposing factors for lung cancer. Overall 25 of 33 patients are in continuous CR with a DFS of 76% (95% CI 67% to 86%) and 26 of 33 patients are alive with an OS of 79% (95% CI 68% to 89%) at 122 months median follow-up (range 86148), respectively (Figures 2 and 3). The probability of relapse for patients achieving CR after ASCT is 16% at 10 years (Figure 4).
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Discussion |
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The recommendation for ASCT as part of first-line therapy, however, is discussed controversially [3, 30
]. As reported previously [24
], we addressed that issue in a phase II study including HDCT and ASCT as part of the up-front treatment in patients being at risk and not achieving sustained CR. In the present study, the long-term follow-up of 33 patients who had undergone HDCT and ASCT as part of the initial treatment was investigated. After ASCT, 94% of the patients achieved CR. Two patients not achieving CR and two patients with relapse at 1 and 6 months after transplantation died due to the underlying disease. Three patients relapsed 31, 55 and 127 months after achieving CR; the third had refused radiotherapy at the site of former bulk disease. No transplantation-related death occurred. This low TRM risk is in contrast to other groups with TRM up to 11% [30
, 31
].
As of 31 December 2003, 25 of 33 patients are in sustained CR with a DFS for all patients of 76%. These data are comparable to other groups using HDCT reporting a DFS between 74 and 81% [3134
]. Sehn et al. reported a prolonged PFS for patients with diffuse large B-cell lymphoma of the mediastinum after HDCT and ASCT [33
]. In grouping patients according to the aaIPI, eight of 11 (73%) patients without risk factors or with one risk factor, and 17 of 22 (77%) with two or three risk factors are in sustained CR at a median follow-up of 10 years. These results are in accordance with those reported by Gianni et al. for patients with DLCL treated with high-dose sequential therapy and aBMT [36
] and Santini et al. [35
], who found a statistical advantage of PFS in patients receiving ASCT after VACOP-B standard therapy compared to VACOP-B alone for patients with two or three risk factors. Overall, these results are better than the results with standard chemotherapy and even dose-intense 2-weekly CHOP therapy [6
, 7
]. Of note, patients refractory to initial chemotherapy,
5% at our institution, were not included in our study. During the median follow-up of 10 years we observed only three late relapses after transplantation (at 31, 55 and 127 months), but relapse beyond 5 years after HDCT has been reported in hgNHL [28
].
Our data are in line with a recently published randomized trial from the French study group GOELAMS [37]. This randomized study compared standard CHOP therapy alone with HDCT and ASCT, preceded by two cycles of CEEP [37
]. The estimated event-free survival (EFS) and OS was significantly higher after HDCT and ASCT as compared to CHOP treatment for patients with two risk factors according to aaIPI but not for patients with only one risk factor (EFS 56% versus 28% and OS 74% versus 44%, respectively) [37
]. Of note, high-risk patients (aaIPI 3) were not included in this randomized trial but treated with HDCT immediately [37
].
The observation that both aaIPI subgroups of our trial were comparable with respect to clinical characteristics other than the aaIPI, make a bias due to an unequal distribution of subsets of patients unlikely. These findings suggest that the expected differences in outcome using the aaIPI were not seen or were abrogated by the use of ASCT. It is possible that in our study population, ASCT led to this improvement in outcomes for the high-risk group while adding nothing to the low-risk group who already have a relatively good prognosis.
We conclude from our study that patients with aggressive, chemosensitive hg B-NHL may benefit from early intensified therapy with HDCT and ASCT in terms of DFS and OS. While other studies demonstrate a prognostic prediction of the aaIPI for patients with relapsed DLCL treated with HDCT and ASCT [10], we observed that long-term DFS and OS after HDCT and ASCT in patients with hg B-NHL, were not significantly correlated to the aaIPI and that the risk of late relapse in this distinct study population is low.
Received for publication March 12, 2004. Revision received May 6, 2004. Accepted for publication May 7, 2004.
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