© 2004 European Society for Medical Oncology
Long-term follow-up after high-dose chemotherapy and autologous stem-cell transplantation for high-grade B-cell lymphoma suggests an improved outcome for high-risk patients with respect to the age-adjusted International Prognostic Index
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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Background: To evaluate the long-term benefit from high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT), as part of the initial treatment for patients with chemosensitive, high-grade B non-Hodgkin's lymphoma (hg B-NHL), stratified according to the age-adjusted International Prognostic Index (aaIPI).
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 86–148) 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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High-grade non-Hodgkin's lymphoma (hgNHL) accounts for 4–6% of all newly diagnosed malignancies per year with increasing incidence in the USA [1
]. Most patients (60–80%) with high-grade B-cell non-Hodgkin's lymphoma (hg B-NHL) respond to primary combination chemotherapy with or without radiotherapy and achieve partial (PR) or complete remission (CR) [2, 3]. However, sustained remission after first-line therapy is only achieved in 40–50% of unselected patient populations [2], in 50–60% of diffuse large cell lymphoma (DLCL) [4] and in 45% of mediastinal large cell and immunoblastic lymphomas [5]. Despite salvage therapies >50% of the patients treated by standard therapy still die due to their underlying disease [5]. Third-generation protocols did not improve the survival as compared to standard CHOP chemotherapy and recently published data with dose-intense, 2-weekly CHOP chemotherapy led to an overall survival (OS) of 60% after a medium follow-up of 5 years [6, 7]. To predict outcome at initial diagnosis before therapy, Coiffier and Lepage described five risk models in patients with aggressive NHL [8]. More recently the International NHL Prognostic Factors Project [9] identified patients at high risk for treatment failure or relapse. The international prognostic index (IPI) has become a routine instrument of risk stratification for patients with high-grade lymphomas [10]. For patients under the age of 60 years, the following three independent risk factors have been identified (aaIPI): performance status (PS) 
2 [Eastern Cooperative Oncology Group (ECOG)], Ann Arbor stage III or IV and elevated serum lactate dehydrogenase (LDH) [10, 11]. Whereas high-dose chemotherapy (HDCT) and autologous stem-cell transplantation (ASCT) is accepted as standard therapy for patients with chemosensitive relapse of hgNHL, the role of HDCT as part of the initial therapy for high-risk NHL is not yet conclusively determined. For patients with high IPI risk score, according to the age-adjusted index, several trials have addressed the role of early HDCT and ASCT in order to reduce the relapse rate [11–14]. Compared to conventional therapy, improved OS in one study [14] or no difference in survival in two studies [15, 16] were observed. Retrospective evaluation after longer follow-up in one trial showed better results for the subgroup of high-risk patients (two and three risk factors according to the IPI) after ASCT with a median follow-up of 5 years [progression-free survival (PFS) 62% versus 30%] [17–19]. 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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Patients and eligibility
Since 1992, ASCT has been offered to patients aged <60 years who fulfilled the following institutional criteria for HDCT: stage III or IV, bulky disease, elevated lactate dehydrogenase (LDH) or failure to achieve CR after standard VACOP-B chemotherapy [20
, 21]. Patients refractory to initial chemotherapy, namely patients not achieving at least stable disease (SD), 
5% at our institution, were not included in this study. Additional eligibility criteria required patients to have a serum creatinine of less than two times the institutional upper normal limit (IUL), bilirubin less than three times the IUL and no evidence for abnormal cardiac function (left ventricular ejection fraction >50%). Patients with Burkitt's or lymphoblastic lymphoma and HIV-related lymphomas were excluded and treated with different protocols. Between January 1992 and March 1997, 33 patients with newly diagnosed hg B-NHL were eligible for the protocol and participated after informed consent. Here we analyze the long-term follow-up of the 33 patients being prospectively treated with consolidative stem-cell transplantation after high-dose chemotherapy as part of our institutional practice. As detailed in Table 1, the study population included 18 male and 15 female patients with a median age of 43.3 years (range 19–56). Histological subtypes were classified according to the World Health Organization (WHO) classification [22, 23].
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Staging procedures
The standard staging procedures included physical examination, ECOG performance status, routine blood analysis with LDH, chest and abdominal computed tomography (CT) scans, abdominal ultrasound and bone marrow smear and biopsy. Other studies, such as magnetic resonance imaging, gastrointestinal endoscopy and cytology of pleural or cerebrospinal fluid were performed in case of clinical suspicion for involvement. All patients with involvement of bone marrow, bone, testes, paranasal sinuses or leukemic disease underwent lumbar puncture and intrathecal therapy with methotrexate (15 mg), dexamethasone (4 mg) and cytosine arabinoside (40 mg) on day 1 of weeks 2, 6 and 10 of the VACOP-B protocol (Table 2). Stable disease was defined as progression or reduction of <50%, partial remission was defined as reduction of
50%, bulky disease as 10 cm in diameter and no detectable disease was considered as complete remission (CR).
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Treatment schedule and ASCT
All eligible hg B-NHL patients were primarily treated according to the VACOP-B protocol (Table 2) [20
, 21]. The first restaging was performed after 6 weeks of therapy. Five of the eligible patients refused to undergo ASCT after 6 weeks. They completed the whole 12-week VACOP-B protocol and were than transferred to transplantation (Table 3). The patients received one (n=22) or two (n=11) cycles of mobilization therapy consisting of VP-16 500 mg/m2, ifosfamide 1500 mg/m2, cisplatin 50 mg/m2 and epirubicin 50 mg/m2 (VIP-E) followed by 5 µg/kg body weight rhG-CSF (Neupogen®, Amgen, Munich) for stem-cell mobilization as reported previously [24]. Stem cells were collected by leukapheresis with a targeted minimum cell count of 2x106 CD 34+ cells/kg body weight for BEAM therapy (BCNU 300 mg/m2, VP-16 8x200 mg/m2, Ara-C 8x200 mg/m2, melphalan 140 mg/m2) and 4x106 CD 34 + cells/kg for BU/CY (busulfan 16 mg/kg, cyclophosphamide 2x60 mg/kg). Cells were cryopreserved without purging or CD 34 + selection. In one patient unmanipulated bone marrow was the source for autologous transplantation; it was collected after 6 weeks VACOP-B and two cycles of mobilization therapy, due to insufficient stem-cell mobilization (Table 3).
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The conditioning regimen was BEAM (n=27) or BU/CY (n=6). Cryopreserved cells were reinfused on day 0. rhG-CSF (Neupogen®) starting on day +1 was administered for rapid neutrophil recovery after transplantation in all patients. Treatment with broad spectrum antibiotics and/or anti-fungal therapy was initiated in case of proven infection or fever above 38°C according to standard institutional guidelines. CMV-negative, leukocyte-filtered and irradiated blood products were given for red cell and platelet support [25
]. After hematological recovery, field radiotherapy (40–50 Gy) for consolidation to the former sites of bulky disease was delivered starting within 6 weeks after transplantation in 9 of 10 patients. In one patient splenectomy was performed after transplantation because of former infiltration; histological examination of the spleen showed no residual disease.
Statistical analysis
Analyses were performed to estimate OS and disease-free survival (DFS), employing the Kaplan–Meier 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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After 6 weeks of the VACOP-B protocol, three of 33 patients (9%) responded but achieved only SD (<50% reduction, no progression), 26 of 33 (79%) achieved PR and four of 33 patients (12%) achieved CR as defined by CT staging criteria (Figure 1). Two of five patients completing 12 weeks standard chemotherapy were afterwards in CR. An additional 10 of 33 patients (30%), who received mobilization therapy with one or two cycles of VIP-E, achieved CR before HDCT, resulting in 16 of 33 patients (48%) transplanted in CR. In six of nine patients (66%) with SD the tumor burden was further reduced by an additional
50%. In 32 of 33 patients (97%) the target numbers of stem cells could be collected after one cycle of VIP-E. One patient relapsed after 12 weeks of VACOP-B therapy between mobilization therapy and ASCT with meningeal manifestation, which was successfully treated by six standard intrathecal therapies before ASCT.
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After HDCT, transplantation with a median cell dose of 5.67 x 106/kg body weight CD 34+ cells (range 1.9–16.4) was performed. Patients engrafted on day +9 median (range 6–16) with a white blood cell count
1 x 109/l and on day +11 median (range 3–23) with unsupported platelets 20 x 109/l. In two patients the platelet count never fell below 20 x 109/l. Maximum WHO treatment-related morbidity (TRM) during VACOP-B therapy, VIP-E and transplantation was grade 3 mucositis, grade 3 fever and in all patients grade 4 neutropenia/thrombocytopenia. No other organ toxicity greater than grade 2 was observed and no patient died due to TRM. 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 86–148), 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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Subgroup analysis with respect to the aaIPI
Multivariate analysis of clinical characteristics including age, gender, histological subtype, bulky disease, renal, hepatic and cardiac function did not demonstrate significant differences between the low-risk (IPI 0/1) and high-risk (IPI 2/3) group, suggesting that both groups were comparable. Eleven of 22 patients with two or three risk factors and five of 11 patients with none or one risk factor were transplanted in CR after VACOP-B therapy and VIP-E mobilization therapy. After transplantation at a median follow-up of 122 months, patients with none or one risk factor have an OS of 81% and patients with two or three risk factors an OS of 77% (not significant) (Figure 2). The DFS analysis demonstrates no significant outcome difference in patients with an IPI of 0/1 versus 2/3 as depicted in Figure 3 (73% versus 77%). Furthermore there is no significant difference for the probability of progression between the risk groups (Figure 4). The two patients never achieving CR had both two or three risk factors.
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Discussion |
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High-dose chemotherapy and autologous stem-cell transplantation is the recommended therapy for relapsed chemosensitive hgNHL patients [28
, 29]. For high-risk patients dose-intense chemotherapy without transplantation results in an OS of 60% at 5 years [7], which could be increased to 73% at 3 years by transplanting patients in partial remission [30]. The expected PFS at 3 years, according to the ‘The International NHL Prognostic Factors Project’, is 83% in patients treated with standard chemotherapy without risk factors, 69% in patients with one risk factor, 46% in patients with two risk factors and 32% in patients with three risk factors [9].
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% [31–34]. 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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