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Journal of Clinical Oncology, Vol 22, No 8 (April 15), 2004: pp. 1460-1468 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.054 Long-Term Follow-Up of Indolent Lymphoma Patients Treated With High-Dose Sequential Chemotherapy and Autografting: Evidence That Durable Molecular and Clinical Remission Frequently Can Be Attained Only in Follicular SubtypesFrom the U.O. Ematologia-Trapianto Midollo Osseo, Istituto Nazionale per Lo Studio e la Cura dei Tumori-Università di Milano, Milano; Dipartimento di Medicina ed Oncologia Sperimentale, Divisione Universitaria di Ematologia-Azienda Ospedaliera San Giovanni Battista; Servizio di Epidemiologia dei Tumori, Università di Torino, Turino; and Divisione di Ematologia, Università di Verona, Verona, Italy Address reprint requests to Paolo Corradini, MD, Hematology, BMT Unit, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy; e-mail: paolo.corradini{at}istitutotumori.mi.it
PURPOSE: To evaluate the prognostic relevance of molecular monitoring of minimal residual disease in indolent lymphomas receiving high-dose sequential chemotherapy and autografting. PATIENTS, MATERIALS, AND METHODS: A polymerase chain reaction- (PCR-)based strategy was used to evaluate the presence of residual tumor cells in a panel of 70 indolent lymphoma patients: 40 with follicular (FCL), 14 with small lymphocytic (SLL), and 16 with mantle-cell (MCL) lymphomas. They were treated either with first-line (n = 61) or second-line (n = 9) therapy with an intensified high-dose chemotherapy program followed by peripheral-blood progenitor cells autografting. The Bcl-1, Bcl-2, and immunoglobulin gene rearrangements were used as lymphoma-specific markers. Overall, a molecular marker was obtained from the diagnostic tissue in 60 of 70 patients (86%). RESULTS: The collection of PCR-negative cells and the achievement of posttransplantation molecular remission (MR) were common in patients with FCL subtype (54% and 70%, respectively), whereas they were not frequent among SLL and MCL (25% and 12.5%, respectively) patients. With a median molecular follow-up of 75 months, an 88% incidence of relapse was observed among patients never attaining MR. In contrast, relapse incidence was only 8% among patients attaining a durable MR (P < .005). At present, 26 patients (20 with FCL and six with non-FCL) are long-term survivors in absence of clinical and molecular disease. CONCLUSION: Our results indicate that among indolent lymphomas, FCL and non-FCL subtypes show a significantly different behavior in terms of MR achievement, and MR after intensive chemotherapy and autografting is predictive for a prolonged disease-free survival, whereas persistent PCR positivity is associated with a high risk of relapse.
High-dose (hd) chemotherapy followed by hematopoietic stem-cell autografting has been used widely as salvage or first-line treatment for aggressive non-Hodgkin’s lymphoma (NHL).1-3 This approach has been used less frequently in indolent NHL, such as small lymphocytic (SLL), follicular (FCL), and mantle-cell (MCL) lymphomas.4-7 Indeed, autografting is considered a complex and risky procedure for neoplasms that often can be handled for long periods of time using conventional chemotherapy and/or radiotherapy. Despite these considerations, intensified treatments aimed at maximal tumor reduction or even disease eradication have been used in young patients with indolent NHL and poor prognostic features with promising, although preliminary, results.8-14 The most important evidence suggesting that intensified cytoreduction may represent a valuable step to improve the outcome of indolent lymphomas comes from the studies on molecular monitoring of minimal residual disease. It has been reported that molecular remission (MR) often can be achieved after hd chemotherapy supported by purged or unmanipulated autologous stem cells.15-19 In addition, patients achieving posttransplantation MR have a lower rate of relapse compared with patients with persistent polymerase chain reaction (PCR) positivity. The molecular status after autologous transplantation has been proposed as an informative prognostic indicator, at least for FCL patients.20-24 The studies regarding minimal residual disease in indolent NHL have been pioneered by the Dana-Farber Cancer Institute group (Boston, MA). Their experience was based on patients receiving autografting as salvage treatment, and the posttransplantation MR in that series was essentially attributed to the use of ex vivo purging of bone marrow (BM) cells with monoclonal antibodies. Disease-free survival was increased in the patients receiving a BM graft successfully purged from residual lymphoma cells. After autografting, the presence of marrow PCR-detectable lymphoma cells was associated with a 48-fold increase in the risk of relapse.4,15,19,22 Subsequent studies have shown that MR can be achieved in a variable proportion of low-grade lymphomas after intensive chemotherapy alone, with no need for ex vivo purging procedures; the intensified hd sequential chemotherapy (i-HDS) regimen used by our group is effective in producing clinical remissions and MRs, as documented in a pilot and a multicenter trial.17,18 We report the long-term molecular analysis performed on a large series of patients, including those with FCL, MCL, and SLL. The results show that a high proportion of FCL patients may attain a durable clinical remission and MR, suggesting that the cure is a reasonable treatment goal, at least for a subset of patients. Conversely, clinical remissions but not MRs were commonly observed in MCL and SLL patients.
Patient Characteristics and Treatment Plan Clinical and molecular data have been collected from 70 patients enrolled onto a multicenter prospective trial using the i-HDS regimen between 1990 and 1999 (Fig 1). The study design was approved by the ethics committee and all patients gave written informed consent to participate. The eligibility criteria were age younger than 60 years; no major organ dysfunction from causes unrelated to lymphoma, including normal cardiac function (systolic ejection fraction > 50%), no chronic respiratory disease, no more than 2.5x the upper limit of normal for liver and renal function tests, no psychiatric disease, and negative HIV test; and ability to provide written, informed consent. All patients provided a written informed consent before starting the program. Disease-related poor performance status was not an exclusion criterion. Histologic diagnoses were revised according to the criteria of Revised European-American Lymphoma classification.25 There were 40 patients with FCL, 14 with SLL, and 16 with MCL; in the FCL subgroup, 11 patients had signs of histologic transformation. All patients were considered to have a high-risk disease if they had one or more of the following prognostic features: tumor-related symptoms (B symptoms or compression symptoms caused by local enlargement of lymph nodes), bone marrow involvement more than 20%, bulky disease (> 5 cm), and signs of histologic transformation. Forty-three percent of patients had an age-adjusted International Prognostic Index score of 2 or higher.26 Only nine of 70 patients received i-HDS as second-line treatment. The clinical and histologic characteristics of the 70 patients are listed in Table 1.
The i-HDS program is shown in Figure 1.17 During the first years of the study (the first 30 patients), it was our policy to perform a BM collection as backup, along with peripheral-blood progenitor cell (PBPC) collection; subsequently, BM collection has been considered only for the few patients with suboptimal amounts of PBPC. Radiotherapy was given on bulky sites approximately 2 months after autografting.
Identification of Molecular Markers
PCR Detection of Residual Lymphoma Cells
Disease Evaluation and Statistical Methods All patients who began to receive treatment were considered assessable for response and outcome on an intention-to-treat basis. Overall survival (OS) was measured from the start of therapy to the date of death or last follow-up. Progression-free survival (PFS) for all patients was taken from the start of therapy until disease progression or death as a result of lymphoma. Disease-free survival (DFS) for patients in CR was measured from the first recording of a CR to the date of progression. Event-free survival (EFS) was calculated from the start of therapy to the first adverse event; that is, relapse or progression, secondary malignancy, treatment-related death, or last follow-up. Follow-up of patients switching to allogeneic transplantation or receiving rituximab consolidation in the absence of overt relapse was stopped at the day on which such a treatment was provided. Patients that concluded the hd sequence but did not undergo the final autografting phase because of refusal or toxicity were included in the analysis. The closing date for analysis was March 31, 2003. OS, DFS, PFS, and EFS were calculated according to the Kaplan and Meier method.29 The log-rank test was used to compare survival curves.30
To identify prognostic variables at i-HDS for OS and EFS, the following clinical and molecular parameters were evaluated in univariate analysis: age (> or
Clinical Response and Long-Term Outcome Sixty of 70 assessable patients (86%) completed the program, whereas 10 patients did not undergo the final autografting phase because of refusal (three patients), hepatitis B reactivation (one patient), occasional discovery of concomitant esophageal cancer (one patient), or disease progression (five patients). Of the 10 patients who did not receive autografting, two achieved CR at the end of HDS; four patients with clinical evidence of disease persistence who had an HLA-identical sibling donor were switched to allogeneic transplantation; the remaining four patients had a rapidly progressive disease. Among 60 patients completing the program, 56 (93%) achieved CR, whereas four (7%) were in PR. One patient in PR underwent an allogeneic transplantation, whereas the other three patients underwent salvage regimens other than i-HDS, with poor outcome. Thus, overall 58 of 70 patients (83%) achieved CR. There was one transplantation-related death: though in CR, this patient was not considered assessable for response. CR rates were not statistically different among different subtypes: 90% in FCL, 79% in SLL, and 75% in MCL. The survival projections, according to the main histologic categories (FCL and non-FCL subtypes) are listed in Figure 2. Overall, at a median follow-up of 90 months (range, 6 to 158 months) 52 (74%) of 70 patients are alive, with an estimated 12-year OS projection of 76% and 49% for FCL and non-FCL, respectively (P < .05). Among the 58 patients in CR, there have been 21 relapses. At present, 37 patients (53%) are alive in continuous CR, with estimated 12-year DFS projections of 66% and 26% for FCL and non-FCL, respectively (P < .01). FCL patients proved to have a significantly better outcome compared with patients with non-FCL subtypes also in terms of PFS (60% v 20% at 12 years; P < .005) and EFS (57% v 17% at 12 years; P < .01).
Among the FCL subtype, the clinical outcome of 11 patients with signs of histologic transformation was also evaluated. The EFS curve of this subgroup is projected to be 54% at 10 years, which is similar to the EFS of the remaining 29 FCL patients (65% at 10 years; P = .57) and significantly better compared with that of non-FCL patients (P < .05). Secondary hematologic malignancies occurred only in three patients with FCL (4%). Two patients developed acute myeloid leukemia, at 4 months and 1 year after autograft, respectively: the first patient died soon after diagnosis, whereas the second is still in CR of her second tumor at 5 years after a second salvage autograft. The third patient developed a diffuse large-cell lymphoma after 42 months of MR achieved by autotransplantation; sequencing analysis of the immunoglobulin heavy-chain genes showed that the rearrangement of immunoglobulin-variable region segments observed at relapse was unrelated to that observed at diagnosis, suggesting the occurrence of a second lymphoma.32
PCR Detection of Residual Lymphoma Cells in PBPC or BM Collections and After Autografting BM obtained before treatment was PCR-positive in all the 60 patients having a marker. A total of 160 PBPC and 46 BM collections were analyzed. In 19 (54%) of 35 FCL patients, one or more PCR-negative BM or PBPC cells were collected. Conversely, PCR-negative cells were collected in only three (12%) of 25 patients with non-FCL subtypes. The collection of one or more PCR-negative cells was associated with a better DFS compared with patients from whom only PCR-positive cells were collected (P < .025; Fig 3A). A similar association also was observed when the DFS evaluation was restricted to FCL patients only (data not shown). The DFS was not different for patients having only some or all PCR-negative cells collected (data not shown). No statistical correlation could be found between the degree of BM infiltration at diagnosis and the PCR negativity of cells collected; however, PCR-negative stem cells were collected from all patients presenting without overt histologic infiltration of the marrow.
Forty-four of 60 patients having a molecular marker underwent long-term molecular monitoring. The median molecular follow-up was 75 months (range, 10 to 144 months). Three different patterns of PCR results were observed: in 19 patients, all follow-up samples were PCR-negative and only one of these patients developed recurrent disease; that patient experienced a localized relapse in the CNS.33 In contrast, 11 relapses were seen in the group of 15 patients with persistent PCR-positive molecular follow-up. In the remaining 10 patients, PCR analysis at different time points revealed a mixed PCR pattern; in this group we observed five relapses. Four of these patients had been autografted with PCR-positive cells, and they experienced relapse after a short PCR-negative follow-up (Fig 3B). The median molecular follow-up was 80 months for PCR-negative patients, 72 months for the mixed group, and 30 months for PCR-positive patients. The achievement of MR was quite common in FCL patients (21 of 30 assessable patients [70%]), whereas it was only occasionally observed among patients with MCL or SLL (five of 20 patients [25%]; P < .025). Among FCL patients, seven had sign of histologic transformation. Six of these seven patients achieved the MR after autografting, and four patients (57%) are still in continuous clinical remission and MR with a molecular follow-up of 86 months.
Prognostic Parameters
This study reports the results of the long-term clinical and molecular monitoring in a series of indolent lymphoma patients undergoing i-HDS chemotherapy followed by PBPC autografting. Most FCL patients achieved MR, although this was an uncommon feature among non-FCL patients. In addition, patients with durable posttransplantation MR had a low risk of disease recurrence. The association between durable PCR negativity and low risk of relapse has been reported for FCL patients autografted with in vitro purged BM cells.19,22,23,34-37 We confirm those results without any in vitro purging procedure. Indeed, the extensive chemotherapy debulking was included in the i-HDS scheme before stem-cell collection with the aim of causing an in vivo purging effect. The schedule was effective in FCL patients, allowing a high rate of PCR-negative harvests with the subsequent achievement of durable posttransplantation MR. The i-HDS regimen was applied not only to patients with FCL, but also to those with MCL and SLL. Different pathways have been identified in the origin of these forms. In particular, FCL, along with most of diffuse large-cell and Burkitt’s lymphomas, belongs to the germinal center (GC)-derived neoplasms, whereas the MCL and SLL subtypes are CD5-positive and derive from cells outside the GC. However, because of the similar clinical behavior, FCL, SLL, and MCL have been clustered for a long time into the indolent lymphoma category. In addition, in our experience, no significant differences were seen in terms of clinical response to i-HDS among histologic subtypes, and high CR rates were recorded in all subgroups. Conversely, marked differences were seen when the molecular response was evaluated. In fact, PCR negativity was a common feature in patients with FCL, whereas it was remarkably unusual among those with SLL and MCL. This suggests that the chemotherapy option might have a curative potential in GC-derived lymphomas, whereas it seems unable to eradicate B-cell tumors arising from pre-GC and post-GC cells. This parallels observations from gene-profiling studies in diffuse large-cell lymphoma, where the GC-derived forms seem to be highly curable as opposed to those displaying an extra-GC gene expression profile.38 In our study we also analyzed the clinical and molecular outcome of i-HDS in a small subgroup of patients with transformed FCL. Using conventional anthracycline-containing regimens, the prognosis of patients with these histologic characteristics is generally poor, with a low response rate and short survival.39-41 With the exception of a subset of patients with a limited and chemosensitive disease, the median survival with cyclophosphamide, doxorubicin, vincristine, and prednisone-like regimens is about 1 year.39,42,43 In an effort to improve response and survival, several centers have investigated the autologous transplantation strategy with a 30% to 50% DFS at 5 years.44-46 In our study, the outcome of patients with transformed lymphoma was encouraging, with an estimated 10-year EFS projection of 54%. The collection of exclusively PCR-positive cells or the persistence of PCR positivity after autografting was associated with a high risk of disease recurrence.47-51 Obviously, not only the attainment of MR, but also its duration are critical factors to determine the clinical outcome. During our longitudinal long-term molecular monitoring, a single relapse was documented in patients persistently PCR-negative after autografting, in contrast to the high number of relapses in those patients who never became PCR-negative. Finally, a small subgroup of patients had mixed PCR results after autografting: in fact, during molecular follow-up, they fluctuated between negative and positive results. The risk of clinical relapse in this latter group was significantly higher compared with that in patients with a persistent PCR negativity. Our findings give additional support to the concept that MR achievement is a worthwhile goal in the treatment of indolent lymphoma. In a previous report, the St Bartholomew’s Hospital group has shown that persistent PCR negativity during molecular follow-up was the strongest predictor of improved outcome in FCL patients undergoing hd chemotherapy and autografting.23 High rates of PCR negativity also have been observed in FCL patients receiving rituximab-containing regimens. However, the predictive value of PCR results after rituximab therapy is still under investigation. In fact there is a prominent effect of the antibody in clearing circulating and marrow lymphoma cells, even in patients with a persistent nodal disease. Conversely, in our experience, all patients attaining the PCR negativity also were in clinical CR. Thus, the combined clinical remission and MR seems to be a prerequisite for a prolonged survival. CR achievement also was associated with a significantly lower risk of death or recurrence. However, given that the vast majority of patients achieved CR, MR identifies more selectively the subgroup with the highest probability of prolonged OS and DFS. Considering the long natural history of the majority of indolent lymphomas, all of the investigators’ trials emphasize the long follow-up required to evaluate the clinical impact of intensive or novel chemotherapy approaches, when compared with conventional treatments.14 Our patients were observed to 12 years; several remain alive in continuous CR. The finding that most FCL patients are long-term survivors in the absence of PCR-detectable disease raises the possibility that the neoplastic clone might have been eradicated in these patients. It is quite reasonable to conceive that patients surviving in the absence of clinical and molecular disease for 5 or more consecutive years might be cured of their lymphoma. Additional studies should be performed for patients not attaining PCR negativity. The inclusion of the rituximab into intensive chemotherapy programs is being investigated currently. The in vivo purging caused by rituximab has been shown to decrease dramatically the number of patients from whom PCR-positive cells are collected in both FCL and MCL.52-54 The addition of rituximab might improve the antitumor efficacy of the intensive approach, and it might allow a reduction of the chemotherapy courses required to achieve the PCR negativity. Another therapeutic option that recently has shown interesting results is the nonmyeloablative conditioning followed by allogeneic transplantation of hematopoietic cells. Although the follow-up is still short, several reports show that treatment-related toxicity has been reduced and that the outcome is promising. In fact, some studies have demonstrated that patients also can attain MR after transplantation.55-57 On the basis of these findings, the allografting option should seriously be considered for the patients enrolled onto autografting programs collecting PCR-positive stem cells. In conclusion, this study shows that molecular monitoring is a feasible approach to obtain clinically relevant prognostic information in indolent lymphomas. PCR negativity in the autologous transplantation setting remains the best indicator for a prolonged DFS. The persistence of molecular disease definitely is associated with a continuous pattern of relapse.
The authors indicated no potential conflicts of interest.
Supported in part by Associazione Italiana Ricerca sul Cancro and Compagnia di San Paolo Programma Oncologia. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
45 years), BM involvement, histologic subtype, histologic transformation, disease status, age-adjusted International Prognostic Index (< 2 or 
2), CR achievement, PCR negativity of collected cells, and MR achievement. These parameters were also evaluated in multivariate analysis using the stepwise Cox regression model.
