Annals of Oncology Advance Access originally published online on January 17, 2007
Annals of Oncology 2007 18(4):652-657; doi:10.1093/annonc/mdl466
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© 2007 European Society for Medical Oncology
hematologic malignancies |
The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience
1 Hospital Universitario Son Dureta (Service of Oncology), Palma
2 Hospital de Valdecilla, Santander
3 Hospital Universitario Son Dureta (Service of Hematology), Palma
4 Hospital La Princesa, Madrid
5 Hospital de Jerez de la Frontera, Cádiz
6 Hospital Nuestra Señora de Aránzazu, San Sebastián
7 Clínica de Navarra, Pamplona
8 Hospital Xeral-Cies, Pontevedra
9 Hospital Clínico de Salamanca, Spain
* Correspondence to: Dr J. Rodríguez, Service of Oncology, University Hospital Son Dureta, Av/Andrea Doria 55, Palma de Mallorca 07014, Spain. Tel: +34-971-175000; Fax: +34-971-175500; E-mail: jrodriguez{at}hsd.es
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Abstract |
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Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor prognosis with standard chemotherapy. Consolidation with autologous stem-cell transplantation (ASCT) may improve survival. We present 74 patients transplanted in first complete response (CR) from the Spanish Lymphoma and Autologous Transplantation Group cooperative group.
Patients and methods: Median age was 46 years. Eighty-eight percent presented advanced (III–IV) Ann Arbor stage; 53% had B symptoms; 52% had high lactate dehydrogenase; 65% had two or three risk factors of the adjusted-International Prognostic Index; 58% presented a high Tumor score and in 14% more than two adverse factors of the Prognostic Index for peripheral T-cell lymphoma (PIT) were observed.
Results: With a median follow-up of 67 months from diagnosis, the 5-year overall survival (OS) was 68% and progression-free survival (PFS) reached 63%. The multivariate analysis showed that the only factor associated with a shorter OS and PFS was the presence of more than two risk factors from the PIT risk system.
Conclusions: In a retrospective study with a prolonged follow-up, consolidation with ASCT in CR patients who had presented unfavorable prognostic factors at diagnosis substantially increased the OS and PFS when compared with conventional chemotherapy. The PIT risk system identified 14% of patients without benefit from ASCT consolidation. Thus, other innovative therapies are still necessary in certain cases.
Key words: autologous stem-cell transplantation, complete response, consolidation, front-line, peripheral T-cell lymphoma
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The T-cell immunophenotype is an unfavorable prognostic factor in aggressive lymphomas. Indeed, the risk of relapse is higher than in the corresponding B-cell lymphomas. Current chemotherapy regimes designed for aggressive lymphomas do not offer major benefits to patients within this group of lymphomas. In fact, the 5-year survival in most studies was around 20%–40% when patients were treated with conventional chemotherapy regimes for aggressive lymphomas [1, 2]. This figure is significantly inferior to that observed in the corresponding B-cell lymphomas [1, 3, 4]. Indeed, in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) LNH87 study the prognosis of the nonanaplastic T-cell lymphomas was worse than that of the B-cell lymphomas. This was, however, only observed in the group with an unfavorable International Prognostic Index (IPI) [2]. Moreover, little clinical benefit is observed in lymphomas of T-cell origin when using the principal drugs employed as part of conventional regimes for aggressive B-cell lymphomas such as doxorubicin and platinum [5].
In the salvage setting most retrospective studies, however, indicate that there is a similar outcome between patients with either aggressive B- or T-cell lymphomas when high-dose chemotherapy and autologous stem-cell transplantation (HDC/ASCT) is employed to consolidate the salvage therapy [6–9]. Thus, given their dismal prognosis and these experiences with salvage therapy, it might be appropriate to implement this therapeutic modality as a consolidation of front-line therapy. There is few data available regarding the use of this HDC/ASCT approach as a first-line therapy. Therefore, we report here the first large retrospective series with the longest follow-up of peripheral T-cell lymphoma (PTCL) patients treated with ASCT as a consolidation of a complete response (CR) to conventional chemotherapy for aggressive lymphoma.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients
From July 1990 to December 2004, the hospitals participating in the Spanish Lymphoma and Autologous Transplantation Group attended 198 patients with PTCL who underwent HDC/ASCT. Patients with severe concomitant medical or psychiatric illnesses, central nervous system involvement or who were human immunodeficiency virus seropositive were considered ineligible for this study. Other criteria for ineligibility included a bilirubin level >1.5 mg/dl, a cardiac ejection fraction of <50% and a pulmonary function test and diffusing lung capacity of <50% of the predictive value. In this report, we retrospectively selected 74 (37%) cases from the register that where front-line consolidated with HCD/ASCT when in CR following conventional chemotherapy.
A histological diagnosis was established by the local pathologist in each center. Expert hematopathologists were consulted in the cases who presented difficult diagnostic features following recommendations of the group. The histological subtypes were as follows: 50% PTCL unspecified (n = 37), 31% anaplastic large T-cell lymphoma (n = 23), 11% angioimmunoblastic T-cell lymphoma (n = 8), 5% lymphoepitheloid T-cell lymphoma (n = 4), 1% hepatosplenic gamma/delta T-cell lymphoma (n = 1) and 1% intestinal T-cell lymphoma (n = 1). The disease stage was evaluated according to the Ann Arbor staging system and the patients were staged according to standard procedures with a physical examination, blood and serum analysis, chest X-rays and computed tomography of the neck, chest, abdomen and pelvis. Bone marrow aspirates and biopsies were obtained before HDC, and other staging procedures were carried out at diagnosis to define the pretransplantation state. Standard variables of the adjusted a-IPI [10] and other variables of known prognostic importance for these types of lymphoma were evaluated [11–13]. The clinical characteristics of the patients at diagnosis are shown in Table 1.
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treatment plan
Pretransplant regimes were not uniform but rather they were mainly anthracycline-based regimes (Table 1). The preparative regimes and other transplant-related factors are shown in Table 2. Accordingly, 54 patients received a BEAM (BcNu, etoposide, cytosine arabinoside, and melphalan) regime (73%); 13 BEAC (BcNu, etoposide, cytosine arabinoside, and cyclophosphamide) (18%); four a CVB (cyclophosphamide, etoposide, and BcNu) regime (5%) and three cyclophosphamide/TBI (total body irradiation) (4%). Similarly, 57 patients received mobilized peripheral blood (PB) as the stem-cell source (77%), 13 bone marrow (18%) and four both (5%). Of the 61 patients that received PB stem cells, 35 were mobilized with growth factor (57%), 24 with growth factor and chemotherapy (39%) and in two cases they were mobilized with chemotherapy alone (3%).
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response and follow-up criteria
The response to therapy was evaluated at 1, 3 and 6 months after transplantation by the investigator responsible in each center and each 6 months thereafter. Evaluations followed the standard guidelines involving a physical examination, complete blood counts, the panel of serum biochemical tests, bone marrow aspiration and biopsy and radiological studies as mentioned above. A CR was defined as the disappearance of all clinical evidence of lymphoma for a minimum of 4 weeks, with no persisting symptoms related to the disease. Before transplantation, complete restaging was carried out in all patients. To categorize a patient as a complete responder after HDC/ASCT, residual masses had to have remained unchanged for 6 months or longer. A partial response was defined as a >50% decrease in the sum of the products of the two longest diameters of all measurable lesions for at least 4 weeks. Likewise, nonmeasurable lesions had to have decreased by at least 50%. Lesions could not have increased in size and no new lesion could have appeared. A progressive disease was defined by any increase >25% in the sum of the diameter of any measurable lesions or the appearance of a new lesion. Transplant-related mortality was defined as death within 100 days of high-dose therapy not related to the disease, relapse or progression. Toxic mortality was considered at any time if it was related to the procedure.
statistical methods
Overall survival (OS) and progression-free survival (PFS) were measured from the date of transplantation and they were estimated according to the Kaplan–Meier method [14]. Comparisons between the variables of interest were carried out by the log-rank test [15]. Multivariate analysis with the variables that appeared to be significant in the univariate analysis was carried out according to the Cox proportional hazards regression model [16]. All P values reported were two-sided and statistical significance was defined at a P value <0.05.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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clinical characteristics at diagnosis
When considering the clinical characteristics of the patients at diagnosis (Table 1), we found that the median age of the patient cohort was 46 years (15–69). Most patients (58%) displayed an Eastern Cooperative Oncology Group performance status of zero or one, and the majority of patients were attributed to the Ann Arbor stage III–IV (88%). Additionally, B symptoms were diagnosed in 53% of the patients. Among those studied, 30% of the individuals exhibited more than one extranodal disease site and a bulky mass was present in 37% of the cases. Other important clinical variables included the elevation of lactate dehydrogenase in 52% of the patients and an increase in ß2-microglobulin in 34%. Data for either of these variables, however, were only available in 69 and 56 cases of the 74 patients.
According to the a-IPI distribution, 65% of the patients displayed more than one factor at diagnosis, while 58% of the patients presented with more than two factors of the tumor score. The new Prognostic Index for peripheral t-cell lymphoma (PIT) risk system was taken as a discrete variable to divide the population into two prognostic groups. In the first of these, the patients displaying zero, one or two factors at diagnosis were included that comprised 86% of the patients. The second group involved 14% of the patients and it was made up of those that presented three or four factors from this risk system at diagnosis.
outcome
At a median follow-up of 67 months from diagnosis (within a range of 8–214 months), 53 of the 74 (72%) patients were alive and thus, the estimated OS at 5 years was 68% (57%–79%) and the PFS at 5 years was 63% (51%–74%, Figure 1). At the last follow-up 21 (28%) patients had died, where 62% of the deaths were due to the disease, 10% to infection and four patients of a second neoplasia. The Transplant-related mortality (TRM) was 4% (n = 3).
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prognostic factors
We analyzed clinical factors that might be associated with the outcome of OS and PFS (Table 3). In a univariate analysis and a Cox proportional hazards regression model, the only factor associated with OS in both univariate and multivariate analysis was the PIT system taken as a discrete covariant. In fact, patients presenting zero, one or a maximum of two factors had a 74% of OS at 5 years when compared with 31% of the patients with more than two factors (P = 0.012). In terms of the PFS end point, apart from the PIT system, patients with bone marrow involvement at diagnosis had 42% PFS at 5 years versus 69% in patients with no bone marrow involvement. Again, however, only the PIT was associated with the PFS in the multivariate analysis with a hazard ratio (HR) of 2.65 (1.1–6.3, Figure 2).
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The results obtained from patients with anaplastic large T-cell lymphoma (T-ALCL) were analyzed and compared with the rest of the cases. We must, however, take into account that there was no data available regarding the expression of Araplastic lymphoma kinase (ALK) in most of our patients with T-ALCL. It has been reported that patients with T-ALCL whose tumor cells express ALK have a remarkably better prognosis than other patients [17]. Thus, our comparison is biased by this lack of information. Nevertheless, as expected on the basis of the frequency of this marker in T-ALCL, we observed an OS at 5 years of 84% versus 61% in patients with anaplastic versus nonanaplastic PTCL subtypes, respectively (P = 0.058). Similarly, the PFS was significantly higher in the anaplastic group (80%) when compared with the other group of patients (55%, P = 0.036). These data indicate that as observed with conventional chemotherapy treatment, patients with T-ALCL perform better than the rest of those with PTCL when ASCT is used as a consolidation therapy in first remission.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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When conventional chemotherapy is employed to treat aggressive lymphomas it has a weaker impact on PTCL than in the corresponding aggressive B-cell lymphomas [1–4]. The results of this retrospective study show a substantial improvement over a prolonged median follow-up (67 months) in patients with high-risk PTCL (88% presenting with an advanced disease and 65% showing high-risk factors in the a-IPI) when CR was consolidated by front-line ASCT. This improvement surpassed that historically achieved patients with this type of lymphoma are treated with conventional treatment of aggressive non-Hodgkin's lymphoma (NHL). In fact, the 68% OS at 5 years is remarkable in our opinion if we take into account the expected OS and PFS in patients with a similar risk status within the a-IPI system [1, 2, 4, 10]. Our retrospective analysis is subject to the typical bias of this type of study. Nevertheless, we consider that our data are sufficiently valid to warrant testing the hypothesis that consolidation with HDC/ASCT in patients with aggressive lymphomas that are complete responders to conventional chemotherapy regimes will improve the outcome, despite the poor prognosis for this subtype of lymphomas.
There is few data available regarding HDC/ASCT in a front-line setting in PTCL when compared with B-cell lymphomas. In the LNH87 study, the GELA group, however, presented relevant data from a subgroup of T-cell lymphoma patients that had obtained a CR with chemotherapy. Following chemotherapy, these patients were randomized to receive ASCT as a consolidation therapy or they continued with the GELA chemotherapy regime for this kind of lymphoma [18]. In contrast to our data, the results from this small cohort of patients did not identify differences in survival. Likewise, this group reported worse results in high-risk patients with aggressive NHL randomized to ASCT when compared with those receiving conventional chemotherapy. These results may, however, reflect the fact that the patients randomized to receive ASCT probably got insufficient chemotherapy before receiving the transplant, therefore nullifying the potential benefit of consolidation with ASCT.
Recently, several prospective trials of patients with PTCL have been reported in the form of abstracts [19–22]. In a study of 75 patients who received ASCT as consolidation of front-line conventional chemotherapy, 49% of them belonged to the higher risk groups of the IPI [19]. Despite the short median observation time of 10 months, 42% of these patients remained in remission. Only 62% of the patients in this study, however, were actually consolidated with ASCT due to disease progression or toxicity. Similarly, in another study carried out on 64 patients consolidated with transplants, 85% of the patients achieved CR after the transplant and excellent rates of disease-free survival were reported [22]. More than 30% of the patients in this series, however, were not eligible for transplant due to the progress of the disease. In a recent series of Spanish patients with PTCL that were due to receive ASCT as a consolidation therapy of an objective response to conventional chemotherapy, the outcome of patients who in fact received the transplant was very good [20]. Fifty-nine percent of the patients, however, did not receive the transplant due to toxicity, disease progress, lack or mobilization or patient decision. In the same vein, an Italian study carried out over the longest median observation time reported the outcome of 54 patients with PTCL, including 17% of the patients with anaplastic large T-cell lymphoma ALK+ [21]. In this series, the PFS and OS at 5 years was 36% and 52%, respectively. Interestingly, and in accordance with the other prospective series, the disease progressed in 29% of the patients during the treatment and they were not in fact transplanted.
Therefore, in all prospective series published so far the percentage of patients who finally were able to receive the transplant ranged from 50% to 70%. Thus, one can infer two main points from these studies. First, that approximately one-third of patients suffer early disease progression and they are therefore ineligible to receive the transplant. Secondly, in the patients who receive the transplant the outcome seems to be superior to that of conventional chemotherapy alone. Our study, although retrospective, confirms this conclusion. In fact, we focused on those patients actually in CR before the transplantation, having received a complete course of chemotherapy. Our data show a 63% PFS at 5 years with a prolonged median follow-up of 67 months from diagnosis. Interestingly, we observed a plateau in the OS and PFS curves, which matches well with the data from the patients that are in fact able to receive the transplant in the aforementioned prospective series. In contrast to our prolonged observation time, most available prospective series have had a very short follow-up period.
Another aspect of our study was to analyze the prognostic factors that might provide valid information about this therapeutic modality. We confirmed the validity of the PIT risk system designed by the Italian group in a retrospective study of patients with PTCL most of whom received conventional chemotherapy treatment [13]. In fact, we were able to identify a small group of patients when we transformed this risk system into a discrete variable, 14% of the whole population with more than two adverse factors of this PIT scoring system, who did significantly worse than the other patients that presented a maximum of two adverse factors. The favorable group displayed a 74% OS and a 69% PFS at 5 years, compared with 31% and 27%, respectively, in the unfavorable group. Therefore, patients who belong to this latter group should be tested for other therapeutic approaches since HDC/ASCT does not seem to offer any advantage over conventional treatment. Thus, it seems that this PIT risk system offers valid information in the front-line HDC/ASCT setting similar to with conventional treatment. Accordingly, this system is able to segregate patients into different risk groups and thereby allow a proper comparison of the results, particularly relevant in randomized studies.
Obviously, many questions remain unanswered since the data available regarding this group of lymphoma patients is scarce. In an era where genomic and proteomic analyses are providing new potential therapeutic targets and new biological prognostic factors, it seems logical to orientate studies of this type of lymphomas in this direction. In this sense, it would be especially relevant to take into account that what we routinely consider as aggressive PTCL is rather an array of clinically, morphologically and probably genetically different diseases. Thus, it is likely that these different entities probably have different therapeutic targets. This fact is particularly relevant in the case of T-ALCL which has been associated with a better prognosis in most studies [2, 17, 23, 24]. Patients with this condition whose tumor cells do not express ALK, however, have the same poor prognosis as for other nonanaplastic histologies [25]. Our study, like other series, fails to provide data regarding this marker in the patients with anaplastic lymphomas, making it impossible to determine the importance of this factor when patients are treated with ASCT. Nevertheless, we observed a better outcome of T-ALCL patients in our series than of the other defined subtypes, indicating that what is indeed observed with conventional chemotherapy continues to be applicable to ASCT.
As mentioned above, preliminary data from prospective studies shows that a major clinical problem in these patients is the early progress of the disease with conventional chemotherapy regimes. Indeed, this makes a considerable number of patients unsuitable for transplantation. Therefore, new regimes with new more specific compounds that are active against these lymphomas should be tested, such as new nucleoside analogues [26], histone-deacetylase inhibitors [27], m-Tor inhibitors [28], either as single drugs or as part of new regimes. Moreover, it has recently been indicated that the main drug used to treat aggressive B-cell lymphoma, doxorubicin, does not exert any benefits in these T-cell lymphomas [5]. This further emphasizes the need to develop new, specific T-cell lymphoma agents.
In conclusion, when PTCL patients who present poor prognosis factors at diagnosis are consolidated with ASCT after having achieved a CR with conventional front-line therapy for aggressive lymphomas, the outcome is clearly superior to that observed in the same patients treated with conventional chemotherapy alone. A randomized prospective study with sufficient power, however, will be necessary to prove these retrospective observations. Indeed, efforts to complete such a study are ongoing. Nonetheless, due to the relatively low frequency of these entities, international efforts will be needed to collect sufficient numbers of patients within trials in order to draw valid conclusions. Finally, the PIT risk system identified 14% of these patients who do not benefit from ASCT consolidation. Thus, other innovative therapies are still necessary in certain cases.
Received for publication October 30, 2006. Accepted for publication November 15, 2006.
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References |
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