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Comparison of four prognostic scores in peripheral T-cell lymphoma
original article
Annals of Oncology 22: 397–404, 2011 doi:10.1093/annonc/mdq359 Published online 14 July 2010
Comparison of four prognostic scores in peripheral T-cell lymphoma G. Gutie´rrez-Garcı´a1, A. Garcı´a-Herrera2, T. Cardesa2, A. Martı´nez2, N. Villamor2, G. Ghita1, A. Martı´nez-Trillos1, L. Colomo2, X. Setoain3, S. Rodrı´guez4, E. Gine´1, E. Campo2 & A. Lo´pez-Guillermo1* Departments of 1Hematology; 2Pathology; 3Nuclear Medicine; 4Radiology, Hospital Clı´nic, Institut de Recerca Biome`dica August Pi i Sunyer, Barcelona, Spain
Received 7 April 2010; revised 14 May 2010; accepted 19 May 2010
Background: To compare the usefulness of four prognostic scores in patients with peripheral T-cell lymphoma (PTCL) from a single institution.
introduction Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of neoplasms that constitute 10% of the lymphoid malignancies in Western countries [1–3], while this proportion is higher in Eastern countries due to epidemiological and genetic reasons [4, 5]. In contrast to B-cell lymphomas, no specific patterns of morphology, immunophenotyping, genetics or gene expression signatures have been recognized in order to properly classify PTCL. Indeed, the etiopathogenesis and the physiological counterpart of the tumor cells are not well understood [1, 2, 6–9]. All these aspects make difficult to categorize the majority of PTCLs. Thus, whereas anaplastic large-cell lymphoma (ALCL), anaplastic lymphoma kinasa (ALK)-positive [10, 11] and angioimmunoblastic lymphoma (AILT) [12, 13] are well-defined entities, the most prevalent form, the so-called peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), is a highly *Correspondence to: Dr A. Lo´pez-Guillermo, Department of Hematology, Hospital Clı´nic, Villarroel 170, 08036 Barcelona, Spain. Tel: +34-932275475; Fax: +34-932275484; E-mail: [email protected]
heterogeneous group of aggressive T-cell lymphoma without a particular clinico-biological profile [14, 15]. It has been noted that the outcome of PTCLs is worse than that of aggressive B-cell lymphomas. In addition, patients with PTCL could not benefit, at least for the moment, of the immunochemotherapy that is the most important advance in the treatment of lymphomas during the last decade. Nevertheless, although the outcome of patients with PTCL is overall dismal, a small proportion of patients with PTCL might respond and even be cured with conventional chemotherapy [5, 16, 17]. Prognostic factors for response and survival in PTCL have been described in numerous studies. More interestingly, a number of prognostic scores have been applied or specifically built up for patients with PTCL. Thus, the International Prognostic Index (IPI) was built up in a large series of aggressive lymphomas, including PTCLs, and works nicely in both B-cell and T-cell neoplasms [18, 19]. However, the usefulness of IPI has been questioned in some studies in which IPI was not able to retain prognostic interest in multivariate analysis [20, 21]. More recently, the Prognostic Index for T-cell lymphoma (PIT) was developed by the ‘Intergruppo Italiano
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
[anaplastic large-cell lymphoma (ALCL) 21, PTCL not otherwise specified 56 and other 44)]. Complete response (CR) rate and 5-year overall survival (OS) were 41% and 31%, respectively. International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), International peripheral T-cell lymphoma Project score (IPTCLP) and modified Prognostic Index for T-cell lymphoma (mPIT) were calculated as in the original references. mPIT was only assembled to 41 patients in whom Ki-67 immunostaining was available. ALCL patients were analyzed separately. Results: Concordance among IPI, PIT and IPTCLP was 52% for low-risk group, 27% for low/intermediate-risk group, 20% for high/intermediate-risk group and 14% for high-risk group. IPI, PIT and IPTCLP predicted CR, with IPI being the best score in logistic regression. Neither Ki-67 immunostaining nor mPIT predicted CR. Five-year OS (low-risk versus intermediate- or high-risk categories) according to IPI, PIT, IPTCLP and mPIT were 52% versus 45%, 75% versus 49%, 58% versus 20% and 39% versus 0%, respectively. IPTCLP was the best score for OS in multivariate analysis. Conclusion: All the scores demonstrated their usefulness to assess the outcome of patients with PTCL, with IPTCLP being the most significant to predict OS. Key words: peripheral T-cell lymphoma, prognostic score, outcome
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Patients and methods: One hundred twenty-one patients (77 male/36 female, median age 53 years) with PTCL
original article
patients and methods patients One hundred twenty-one patients consecutively diagnosed with PTCL according to the World Health Organization (WHO) classification, from March 1990 to October 2008, and followed up in a single institution were selected for the present study. Most patients, but three (black African, Indian and Hispanic South American) were Spaniard with Caucasian origin. The distribution according to the histology subtypes was as follows: PTCL-NOS 56 (47%), ALK-positive ALCL 21 (17%), AITL 19 (16%), extranodal natural killer (NK)/T-cell lymphoma nasal type 15 (12%), hepatosplenic T-cell lymphoma (HSTL) 7 (6%) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) 3 (2%). Patients with ALK-positive ALCL were analyzed separately because of its particular behavior. Thus, the remaining 100 patients constituted the subjects of the present study. Staging maneuvers included patient history and physical examination (including Waldeyer’s ring area), blood cell counts and serum biochemistry, including LDH and b2-microglobulin (b2-m) levels, computerized tomography scan of chest, abdomen and pelvis, as well as BM biopsy. Post-therapy restaging consisted of the repetition of the previously observed test and/or biopsies. Response was assessed according to conventional criteria. Main initial characteristics of the patients, excluding ALK-positive ALCL, are listed in Table 1. Median age of the patients was 55 years (range 17–84 years) and the male/female distribution was 64/36. Performance status [Eastern Cooperative Oncology Group (ECOG)] more than one was observed in 40 cases (40%), advanced stage (Ann Arbor III or IV) in 81 cases (81%), any extranodal involvement in 76 cases (76%), including BM infiltration in 39 cases (39%), high serum lactic acid dehydrogenase (LDH) levels in 56 cases (56%) and platelet count <150 · 109/l in 28 cases (28%), and 56 (72%) patients of 78 with available data had high b2-m levels. Ninety-one (91%) patients were treated with adriamycin-containing chemotherapy, including 21 (21%) patients who received high dose of chemotherapy followed by stem cell transplantation as part of the first-line therapy. Response to treatment was as follows: CR was 36 cases (36%), partial response was 20 (20%) and failure to therapy was 44 (44%). Median follow-up was 3.9 years (range 2.8–5 years) for surviving patients. Five-year progression-free survival (PFS) of the series was 10% [95% confidence interval (CI) 4% to 16%] (Figure 1). Seventy-six patients had died during
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Table 1. Main features of 100 patients with PTCL at diagnosis (ALCL, ALK+ excluded) N
100
Age Median (range) £60 years Gender, n (%) Female Male, n (%) Histology, n (%) PTCL-NOS AILT NK/T-cell lymphomas HSTL SPTCL Ki-67 >75%a, n (%) Poor performance status (ECOG >1), n (%) B symptoms, n (%) Extranodal involvement ‡2 sites, n (%) Bone marrow involvement, n (%) Ann Arbor stage III–IV, n (%) High serum LDH, n (%) High serum b2-mb, n (%) Platelet cell count <150 · 109/l, n (%) First-line treatment, n (%)
55 (17–84) 63 (63) 36 (36) 64 (64) 56 19 15 7 3 8 40
(56) (19) (15) (7) (3) (20) (40)
52 (52) 37 (37) 39 81 56 56 28
(39) (81) (56) (72) (28)
9 (9) 91 (91) 36 (36) 20 (20) 44 (44)
a
Ki-67 count was available in 41 cases. b2-m levels was available in 78 cases. b2-m, b2-microglobulin; AILT, angioimmunoblastic lymphoma; ALCL, anaplastic large-cell lymphoma; CHOP, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone; ECOG, Eastern Cooperative Oncology Group; HSTL, hepatosplenic T-cell lymphoma; LDH, lactate dehydrogenase; NK, natural killer; PTCL, peripheral T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; SPTCL, subcutaneous panniculitis-like T-cell lymphoma. b
the follow-up, with a 5-year overall survival (OS) of 25% (95% CI 17% to 33%) (Figure 1). Five-year OS according to the histological subtypes was the following: ALK-positive ALCL, 55%; PTCL-NOS, 37%; AILT, 6% and 0% for extranodal NK/T-cell lymphoma nasal type, HSTL and SPTCL. As expected, 5-year OS of ALK-positive ALCL, was significantly high than that of the remainder PTCL (55% versus 25%, P = 0.003). The main initial and evolutive variables, including the histological parameters below indicated, were recorded and analyzed for prognosis.
histologic features The diagnosis of PTCL was based in all the cases on the criteria established in the WHO classification [1]. All the histologic slides were reviewed by at least two of different observers (AM, LC, AG-H and EC). Immunohistochemical stainings were carried out in all cases on paraffinembedded tissues, and the panel of monoclonal antibodies included antibodies against the following antigens: CD2, CD3, CD4, CD5, CD7, CD8,
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Linfomi’ for patients with PTCL-NOS based on age, performance status, serum lactate dehydrogenase (LDH) levels and bone marrow (BM) involvement [20]. This index was modified by the same group [modified Prognostic Index for T-cell lymphoma (mPIT)] changing BM involvement by the proliferation index as assessed by Ki-67 immunostaining [21]. PIT model might have superior capacity to predict the outcome in comparison with IPI, although this fact has not been completely confirmed [21–23]. The newest score was presented by the International peripheral T-cell lymphoma Project (IPTCLP) in the group of patients with PTCL-NOS and AITL [23] and takes into consideration age, performance status and platelet count as main variables. The four scores are able to predict the outcome of PTCL patients, but a comparative study of all the models in a homogeneous series of patients have never been addressed before. In this setting, the aim of the present study was to analyze the main clinico-biological features and outcome of patients with PTCLs from a single institution and to apply the above-mentioned indexes in order to systematically compare their predictive importance.
Annals of Oncology
original article
Annals of Oncology
Table 2. Variables used to calculate the different prognostic scores
Age (£60 versus >60) ECOG (£1 versus >1) LDH (normal versus high) Ann Arbor stage (I–II versus III–IV) Extranodal involvement (<2 versus ‡2 sites) BM involvement (negative versus positive) Platelet cell count (£150 versus >150 · 109/l) Ki-67 (%) (£75 versus >75) Figure 1. Overall survival (OS) and progression-free survival (PFS) of 100 patients with peripheral T-cell lymphoma (anaplastic large-cell lymphoma, ALK+ excluded).
prognostic scores in PTCL The following scores, previously described, were applied to the present series: IPI, PIT, IPTCLP and mPIT. The IPI was calculated according to the International Non-Hodgkin’s Lymphoma Prognostic Factors Project [18]. The variables used were age (£60 versus >60), performance status ECOG (£1 versus >2), LDH level (low versus high), Ann Arbor stage (I–II versus III–IV) and extranodal involvement (£1 versus >2). Four risk groups were defined by IPI: score 0–1, low risk; score 2, low-intermediate risk; score 3, high-intermediate risk and score 4–5, high risk. The PIT score was calculated as detailed by the ‘Intergruppo Italiano Linfomi’ [20]. Four variables were used to build up this score: age (£60 versus >60), performance status (ECOG £1 versus >2), LDH level (low versus high) and BM involvement (negative versus positive). Depending on the number of adverse prognostic factors (0, 1, 2 or ‡3), patients were classified into low-, low-intermediate-, high-intermediate- or high-risk groups, respectively. The IPTCLP score was calculated as detailed by the International PTCL Clinical and Pathology Review Project [23]. Three variables were used to construct this score: age (£60 versus >60), performance status (ECOG £1 versus >2) and platelet cell count (<150 · 109/l versus ‡150 · 109/l). Depending on the number of adverse prognostic factors (0, 1, 2 or 3), patients were classified into low-risk, low-intermediate-risk, high-intermediate-risk or high-risk groups, respectively. The mPIT score was calculated as detailed by the ‘Intergruppo Italiano Linfomi’ [21]. Four variables were used to constructed this score, three of them also being included in PIT (age, ECOG and LDH level) and Ki-67 immunostaining (<75% versus ‡75%). Depending on the number of adverse prognostic factors (0–1, 2 or ‡3), patients were classified into low-, intermediate- or high-risk groups, respectively. IPI, PIT and IPTCLP scores were assessed in all the cases, whereas mPIT was only assembled to 41 patients in whom Ki-67 immunostaining was available. No differences were observed in terms of response, PFS or OS
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PITb
IPTCLPc
mPITd
X X X X
X X X
X X
X X X
X X X X
Group risk were defined: a Four groups: 0–1, low; 2, low-intermediate; 3, high-intermediate and 4–5, high. b Four groups: 1, low; 2, low-intermediate; 3, high-intermediate and 3–4, high. c Four groups: 0, low; 1, low-intermediate; 2, high-intermediate and 3, high. d Three groups: 0–1, low; 2, intermediate and 3–4, high. BM, bone marrow; IPI, International Prognostic Index; ECOG, Eastern Cooperative Oncology Group; IPTCLP, International peripheral T-cell lymphoma Project; LDH, lactate dehydrogenase; mPIT, modified Prognostic Index for T-cell lymphoma. between patients with mPIT assembled and those in whom this score was not available. A summary of the variables used in the different scores is showed in Table 2.
statistical analysis Categorical data were compared using Fisher’s exact test and two-sided P value, whereas for ordinal data, nonparametric tests were used. The multivariate analysis of the variables predicting response was carried out by using a logistic regression. The definitions of CR, PFS and OS were the standard [24]. The actuarial survival analysis was carried out according to the method described by Kaplan and Meier [25] and the curves compared by the log-rank test [26]. The multivariate analysis for survival was carried out by using the stepwise proportional hazards model (Cox) [27].
results distribution according to the PTCL scores The distribution of the patients according to the risk group after applying the different scores is detailed in Table 3. The PIT score allocated a minor proportion of patients 16 (16%) in the low-risk group. The IPI, PIT and IPTCLP score had a similar proportion of the patients in the intermediate risk group 57 (57%), 62 (62%) and 64 (64%) respectively. At the high-risk group, the IPTCLP score allocated a minor number of cases 7 (7%). Regarding the modified PIT, this score showed a particular distribution with a majority proportion (56%) of the patients in low-risk group. Overall concordance among the three scoring systems (IPI, PIT and PTCLP) was 27%. Twentyseven patients were allocated to the same risk group with all the indexes. Total concordance in the three scores was 52% for low-risk, 27% for low/intermediate-risk, 20% for high/ intermediate-risk and 14% for high-risk groups.
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CD16, CD56, CD57, g-B, PF, bF-1/T-cell receptor (TCR)-b, TCR-d1 and BCL-2. Proliferation index was assessed by means of Ki-67 immunostaining and was evaluated in a semiquantitative manner after the observers studied the whole immunostained slide, scoring at least 200 cells in well-preserved areas. Samples were stratified into five groups: 1 (0% to <10% of the tumor cells were stained), 2 (10%–25%), 3 (25%–50%), 4 (50%–75%) and 5 (>75% positive cells). The cut-off used for prognostic issues and to build up the mPIT was 75%, similar to that originally described [21].
IPIa
original article
Annals of Oncology
Table 3. CR, PFS and OS according to the different prognostic scores and its distribution (ALCL, ALK+ excluded) N (%)
CR rate (%)
5-year PFS (%)
5-year OS (%)
Whole group IPI Low risk Low-intermediate risk High-intermediate risk High risk PIT Low risk Low-intermediate risk High-intermediate risk High risk IPTCLP Low risk Low-intermediate risk High-intermediate risk High risk mPITa Low risk Intermediate risk High risk
100 (100)
36
10
25
21 27 30 22
(21) (27) (30) (22)
36 33 17 14
24 15 0 0
52 25 20 0
16 27 36 22
(16) (27) (36) (22)
25 31 33 11
29 13 4 0
75 30 19 0
29 44 20 7
(29) (44) (20) (7)
31 52 14 3
23 6 0 0
58 15 5 0
24 (58) 8 (20) 9 (22)
57 7 36
10 0 0
39 0 0
a
mPIT was available in 41 cases. ALCL, anaplastic large-cell lymphoma; CR, complete response; IPI, International Prognostic Index; IPTCLP, International peripheral T-cell lymphoma Project; mPIT, modified Prognostic Index for T-cell lymphoma; OS, overall survival; PFS, progression-free survival.
response to treatment As previously indicated, CR rate of the series was 36%. Variables predicting for CR achievement were absence of B symptoms, ECOG <2 and platelet count >150 · 109/l. No difference was found in CR rate between patients who received or not adriamycin-containing chemotherapy. In addition, Ki-67 immunostaining was not able to significantly predict CR. Moreover, mPIT was not able to predict response to therapy in the 41 patients with this information available. IPI (P = 0.008), PIT (P = 0.03) and IPTCLP (P = 0.0001) scores predicted CR achievement, as detailed in Table 3. In Table 4, the same information is listed restricted to patients £65 years. A logistic regression analysis was carried out , including the three scores [IPI (low versus intermediate/high), PIT (low versus intermediate/high) and IPTCLP (low versus intermediate/ high)]. In the final model with 100 cases, IPI was the only score with capacity to predict CR achievement [relative risk (RR) = 2.45 (95% CI 1.27–3.63), P = 0.05]. progression-free survival Eighty-seven of 100 patients eventually progressed, including 24 of the 36 patients who had reached a CR. The 5-year PFS was 10% (95% CI 4% to 16%). Variables predicting poor PFS were presence of B symptoms, poor performance status (ECOG ‡2), platelet count <150 · 109/l and high serum LDH levels. IPI (P = 0.001), PIT (P = 0.001), PTCLP (P = 0.001) and mPIT (P = 0.05) also significantly predicted PFS, as detailed in Table 3 and
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Prognostic scores
N (%)
CR rate (%)
5-year PFS (%)
5-year OS (%)
Whole group IPI Low risk Low-intermediate risk High-intermediate risk High risk PIT Low risk Low-intermediate risk High-intermediate risk High risk IPTCL Low risk Low-intermediate risk High-intermediate risk High risk mPITa Low risk Intermediate risk High risk
74 (100)
39
14
30
19 22 20 13
(26) (30) (27) (17)
38 38 14 10
32 16 0 0
58 29 22 0
16 23 23 12
(22) (31) (31) (16)
31 34 28 7
29 15 10 0
75 30 15 0
29 32 11 2
(39) (43) (15) (3)
38 52 7 3
23 9 0 0
58 15 5 0
23 (80) 3 (20) 3 (20)
78 0 22
10 0 0
41 0 0
a
mPIT was available in 29 cases. ALCL, anaplastic large-cell lymphoma; CR, complete response; IPI, International Prognostic Index; mPIT, modified Prognostic Index for T-cell lymphoma; OS, overall survival; PFS, progression-free survival.
plotted in Figure 2. In Table 4, the same results are indicated for patients £65 years. A multivariate analysis was carried out including IPI, PIT and IPTCLP scores. In the final model with 100 cases, PIT was the most important variable to predict PFS [RR = 0.43 (95% CI 0.23–0.82), P = 0.01].
overall survival Seventeen (17%) patients died within 4 months from diagnosis and were considered as early death. Patients with intermediate or high-risk IPI, PIT, IPTCLP or mPIT had higher probability of early death than those with low-risk score (IPI: 82% versus 12%, P = 0.16; PIT: 100% versus 0%, P = 0.04; IPTCLP: 100% versus 0%, P = 0.004 or mPIT: 71% versus 29%, P = 0.07, respectively). Overall, 75 patients died during the follow-up, with a 5-year OS of 25% (95% CI 17% to 33). Unfavorable variables predicting OS were age >60 years, presence of B symptoms, poor performance status (ECOG ‡2), advanced Ann Arbor stage (III–IV), thrombocytopenia (platelet count <150 · 109/l), high serum LDH levels and high serum b2-m level. Ki-67 immunostaining and adriamycin-containing chemotherapy did not reach significance value predicting OS. IPI, PIT, IPTCLP and mPIT showed high value to predict OS, as detailed in Table 3 and plotted in Figure 3. In Table 4, the same data are detailed restricted to patients £65 years. A multivariate analysis was carried out including IPI (low versus intermediate/high), PIT (low versus intermediate/high) and IPTCLP (low versus
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Prognostic scores
Table 4. CR, PFS and OS according to the different prognostic scores and its distribution in patients with age £65 years (ALCL, ALK+ excluded)
original article
Annals of Oncology
intermediate/high). In the final model with 100 cases, IPTCLP was the most important variable to predict OS [RR = 3.52 (95% CI 2.01–7.12), P = 0.0001]. The same analysis was carried out only in the 56 patients diagnosed with PTCL-NOS, with IPTCLP maintaining the prognostic interest in this subset [RR = 7.69 (95% CI 2.21–13.17), P = 0.002].
PTCL scores in ALCL The different scores were applied to the 21 patients with ALKpositive ALCL. CR rate according to different scores was IPI (low-risk versus intermediate/high-risk group) 79% versus 21%, PIT (low-risk versus intermediate/high-risk group) 65% versus 35%, PTCLP (low-risk versus intermediate/high-risk group) 86% versus 14% (low-risk versus intermediate/high-risk group) and mPIT (low-risk versus intermediate/high-risk group) 100% versus 0%. Five-year OS of ALCL patients was 55% (95% CI 35% to 55%). PTCLP was the most important prognostic score for PFS. The four indexes (low-risk group versus intermediate/high-risk groups) also had a high value to predict OS: IPI, 90% versus 20% (P = 0.001); PIT, 100% versus
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20% (P = 0.001); PTCLP, 92% versus 11% (P = 0.0001) and mPIT, 100% versus 0% (P = 0.002).
discussion The outcome of the patients with PTCL, after excluding cutaneous forms and ALCL, is overall dismal. Thus, whereas during the last decade the introduction of immunochemotherapy has resulted in a dramatic improvement of the prognosis of aggressive B-cell lymphomas [28–30], no substantial advance was observed in patients with PTCL[31]. Since the results with chemotherapy are uniformly poor, more intensive treatments have been assayed, including autologous and allogeneic stem cell transplantation in order to improve these figures [32–37]. However, although experimental approaches might be useful in a selected subset of younger patients, morbidity and mortality associated to these procedures are still high. Therefore, the selection of high-risk patients is of paramount importance in this setting. Moreover, in all the PTCL series, there is a small proportion of patients who can survive for long periods of time or even be cured with
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Figure 2. Progression-free survival of the patients with peripheral T-cell lymphoma (anaplastic large-cell lymphoma, ALK+ excluded) according to the different scores: (A) International Prognostic Index (IPI), P = 0.001; (B) International peripheral T-cell lymphoma Project score (IPTCLP), P = 0.001; (C) PIT, P = 0.001 and (D) modified Prognostic Index for T-cell lymphoma (mPIT), P = 0.05. Four risk groups for IPI, IPTCLP and PIT scores: low risk (L), low/intermediate risk (L/I), high/intermediate risk (H/I) and high risk (H). Three risk groups for mPIT score: low (L), intermediate (I) and high (H).
original article
Annals of Oncology
chemotherapy [16, 17, 23]. The identification of this group of potentially curable patients is also needed. Several studies have been addressed to identify prognostic factors in patients with PTCL [11, 13, 20, 21, 38, 39]. Regarding prognostic score systems, IPI was initially designed for its use in aggressive lymphomas, including T-cell lymphomas. IPI is easy to apply in the clinical practice and seemed useful to separate prognostic groups in PTCLs. However, the real value of IPI has been questioned in other PTCL series [4, 20–23, 40]. For this reason, several authors have proposed different prognostic scores, including IPTCLP, PIT and mPIT, to be used specifically in patients diagnosed with PTCL or even in specific histologic subtypes. Nevertheless, as it can be seen in Table 2, the parameters chosen to build up these scores are essentially the same. All four scores are based in clinical variables, with the mPIT being the only one that takes into consideration a biological parameter, the proliferation as assessed by Ki-67 immunostaining. The aim of the present study was to compare the usefulness of the four scores in predicting response with therapy, PFS and OS. No dramatic differences were observed among the indices, although in the multivariate analysis IPTCL showed to be somehow better than the others to predict OS.
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The mPIT was assessed in only one-half of the patients in whom Ki-67 immunostaining was available, with this preventing its comparison with the other scores. Nevertheless, Ki-67 immunostaining was not able to predict response to therapy and its ability to predict OS was scarce in the present series. This is of note because the prognostic role of proliferation has been recently suggested in two different studies [11, 13, 21]. The relatively small number of cases and the histologic selection could explain this discrepancy. The four scores in this article analyzed divided PTCL patients in three or four prognostic categories. However, as it can be observed in Figures 2 and 3, the low-risk group, whatever the score used, emerged as a category clearly separated from the others. This is in agreement with the original papers [20, 21, 23] and it is clinically relevant. Of note, the low-risk group included the vast majority of long survivors. Nevertheless, young patients of any of the intermediate- or high-risk categories are probably candidates to experimental and/or intensive treatments. Whether or not the approach to low-risk patients could be more conservative is a subject of discussion. In fact, at the light of the present results, even these low-risk patients most likely will relapse.
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Figure 3. Overall survival of the patients with peripheral T-cell lymphoma (anaplastic large-cell lymphoma, ALK+ excluded) according to the different scores: (A) International Prognostic Index (IPI), P < 0.0001; (B) International peripheral T-cell lymphoma Project score (IPTCLP), P < 0.0001; (C) PIT, P < 0.0001 and (D) modified Prognostic Index for T-cell lymphoma (mPIT), P = 0.005. Four risk groups for IPI, IPTCLP and PIT scores: low risk (L), low/ intermediate risk (L/I), high/intermediate risk (H/I) and high risk (H). Three risk groups for mPIT score: low (L), intermediate (I) and high (H).
original article
Annals of Oncology
funding Spanish Ministry of Health and ‘Red Tema´tica de Investigacio´n Cooperativa en Ca´ncer’ (FIS-IP07/0409); Instituto de Salud Carlos III (RD06/0020/0051).
disclosure None of the authors declare conflicts of interest.
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references 1. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer 2008. 2. Ascani S, Zinzani PL, Gherlinzoni F et al. Peripheral T-cell lymphomas. Clinicopathologic study of 168 cases diagnosed according to the R.E.A.L. classification. Ann Oncol 1997; 8: 583–592. 3. Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the nonHodgkin’s lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 1998; 9: 717–720. 4. Au WY, Ma SY, Chim CS et al. Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years. Ann Oncol 2005; 16: 206–214. 5. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–4130. 6. Lopez-Guillermo A, Cid J, Salar A et al. Peripheral T-cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. classification. Ann Oncol 1998; 9: 849–855. 7. O’Leary H, Savage KJ. The spectrum of peripheral T-cell lymphomas. Curr Opin Hematol 2009; 16: 292–298. 8. de Leval L, Bisig B, Thielen C et al. Molecular classification of T-cell lymphomas. Crit Rev Oncol Hematol 2009; 72: 125–143. 9. Rodriguez J, Gutierrez A, Martinez-Delgado B, Perez-Manga G. Current and future aggressive peripheral T-cell lymphoma treatment paradigms, biological features and therapeutic molecular targets. Crit Rev Oncol Hematol 2009; 71: 181–198. 10. Fornari A, Piva R, Chiarle R et al. Anaplastic large cell lymphoma: one or more entities among T-cell lymphoma? Hematol Oncol 2009; 27: 161–170. 11. Piva R, Agnelli L, Pellegrino E et al. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. J Clin Oncol 2010; 28: 1583–1590. 12. Dunleavy K, Davis RE, Landgren O et al. BCL-6 and rituximab in diffuse large B-cell lymphoma: where are we? Blood 2007; 109: 843–844; discussion 844–845. 13. Iqbal J, Weisenburger DD, Greiner TC et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 2010; 115: 1026–1036. 14. Agostinelli C, Piccaluga PP, Went P et al. Peripheral T cell lymphoma, not otherwise specified: the stuff of genes, dreams and therapies. J Clin Pathol 2008; 61: 1160–1167. 15. Rodriguez-Abreu D, Filho VB, Zucca E. Peripheral T-cell lymphomas, unspecified (or not otherwise specified): a review. Hematol Oncol 2008; 26: 8–20. 16. Savage KJ. Peripheral T-cell lymphomas. Blood Rev 2007; 21: 201–216. 17. Rudiger T, Weisenburger DD, Anderson JR et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 2002; 13: 140–149. 18. The International Non-Hodgkin’s Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–994. 19. Gisselbrecht C, Gaulard P, Lepage E et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin’s lymphomas. Groupe d’Etudes des Lymphomes de l’Adulte (GELA). Blood 1998; 92: 76–82. 20. Gallamini A, Stelitano C, Calvi R et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004; 103: 2474–2479. 21. Went P, Agostinelli C, Gallamini A et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006; 24: 2472–2479. 22. Lee Y, Uhm JE, Lee HY et al. Clinical features and prognostic factors of patients with ‘‘peripheral T cell lymphoma, unspecified’’. Ann Hematol 2009; 88: 111–119.
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In this study, as in others of the literature, we have considered patients with PTCL as a whole, with only ALCL being separately analyzed. However, this is not entirely correct because the definition of PTCL integrates >15 different categories in the WHO classification. These categories, although sharing a common T-cell origin and an aggressive behavior with poor outcome, have particular clinico-biological personality [1]. Some attempts to define specific scores for particular histological categories have been published (NK/ T-cell nasal type, ATLL and PTCL-NOS, etc.) [20, 21, 41, 42]. All the scores worked well in the PTCL-NOS, the largest group within PTCLs. The number of patients in other histological categories was too small to raise any conclusion. Finally, it is of note that in the group of patients with ALCL, all the scores were useful to define prognosis as well. The treatment given to our patients was quite homogeneous: >90% of them received adriamycin-containing regimens, in most cases combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Indeed, 20% of selected young patients were treated with intensive therapy. All the prognostic scores worked in the subpopulation treated with CHOP (data not shown). The influence of therapy on the prognostic factors of the patients is a well-known fact. Thus, the use of more effective treatments in PTCL, including new drugs, allogeneic stem cell transplantation or biological response modifiers, could result in an improvement of the outcome of the patients, as well as in a change of the variables predicting response and survival. Therefore, the usefulness of the PTCL scores in patients receiving new therapeutic approaches has to be demonstrated in future studies. The knowledge of PTCLs has considerably improved in recent years, thanks in part to the gene expression profile studies [11, 13, 38, 39]. Besides the diagnostic and etiopathogenic importance, these biological features probably have prognostic and therapeutic interest. For instance, gene expression profile allows to distinguish differentiate prognostic molecular subsets in AILT: a poor-prognosis group with two gene signatures associated with immunosuppressive functions and proliferative signals and a good-prognosis group with transcripts that have inhibitory effects on myeloid cell functions, associated with B cells or encode members of the ribosomal protein synthesis pathway. Hopefully, in the next future, some of the biological data could improve the predictive capacity of current scores [13]. In conclusion, all the four scores analyzed demonstrated their usefulness in predicting response and survival in patients with PTCL, although IPTCLP was the most significant to predict OS.
original article
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34. 35.
36.
37. 38.
39.
40.
41.
42.
analysis by the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Ann Oncol 2004; 15: 1790–1797. Jantunen E, D’Amore F. Stem cell transplantation for peripheral T-cell lymphomas. Leuk Lymphoma 2004; 45: 441–446. Corradini P, Tarella C, Zallio F et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia 2006; 20: 1533–1538. Smith SD, Bolwell BJ, Rybicki LA et al. Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen. Bone Marrow Transplant 2007; 40: 239–243. Paolo C, Lucia F, Anna D. Hematopoietic stem cell transplantation in peripheral T-cell lymphomas. Leuk Lymphoma 2007; 48: 1496–1501. Cuadros M, Dave SS, Jaffe ES et al. Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas. J Clin Oncol 2007; 25: 3321–3329. Ballester B, Ramuz O, Gisselbrecht C et al. Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas. Oncogene 2006; 25: 1560–1570. Aviles A, Diaz NR, Neri N et al. Angiocentric nasal T/natural killer cell lymphoma: a single centre study of prognostic factors in 108 patients. Clin Lab Haematol 2000; 22: 215–220. Lee J, Park YH, Kim WS et al. Extranodal nasal type NK/T-cell lymphoma: elucidating clinical prognostic factors for risk-based stratification of therapy. Eur J Cancer 2005; 41: 1402–1408. Suzumiya J, Ohshima K, Tamura K et al. The International Prognostic Index predicts outcome in aggressive adult T-cell leukemia/lymphoma: analysis of 126 patients from the International Peripheral T-Cell Lymphoma Project. Ann Oncol 2009; 20: 715–721.
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23. Vose J. International Peripheral T-cell Lymphoma (PTCL) Clinical and Pathology Review Project: poor outcome by prognostic indices and lack of efficacy with anthracyclines. Blood 2005; 106: 811a. 24. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–586. 25. Kaplan GL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. P 26. Peto R, Pike MC. Conservatism of the approximation (O-E)2/E in the logrank test for survival data or tumour incidence data. Biometrics 1973; 29: 759–784. 27. Cox DR. Regression models and life tables. J R Stat Assoc 1972; 34: 187–220. 28. Coiffier B. State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 2005; 23: 6387–6393. 29. Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117–4126. 30. Pfreundschuh M, Schubert J, Ziepert M et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9: 105–116. 31. Gisselbrecht C. Molecular signatures in T-cell lymphoma. Blood 2010; 115: 919–920. 32. Mercadal S, Briones J, Xicoy B et al. Intensive chemotherapy (high-dose CHOP/ ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 2008; 19: 958–963. 33. Mounier N, Gisselbrecht C, Briere J et al. All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: a matched-control
Annals of Oncology
Annals of Oncology 22: 397–404, 2011 doi:10.1093/annonc/mdq359 Published online 14 July 2010
Comparison of four prognostic scores in peripheral T-cell lymphoma G. Gutie´rrez-Garcı´a1, A. Garcı´a-Herrera2, T. Cardesa2, A. Martı´nez2, N. Villamor2, G. Ghita1, A. Martı´nez-Trillos1, L. Colomo2, X. Setoain3, S. Rodrı´guez4, E. Gine´1, E. Campo2 & A. Lo´pez-Guillermo1* Departments of 1Hematology; 2Pathology; 3Nuclear Medicine; 4Radiology, Hospital Clı´nic, Institut de Recerca Biome`dica August Pi i Sunyer, Barcelona, Spain
Received 7 April 2010; revised 14 May 2010; accepted 19 May 2010
Background: To compare the usefulness of four prognostic scores in patients with peripheral T-cell lymphoma (PTCL) from a single institution.
introduction Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of neoplasms that constitute 10% of the lymphoid malignancies in Western countries [1–3], while this proportion is higher in Eastern countries due to epidemiological and genetic reasons [4, 5]. In contrast to B-cell lymphomas, no specific patterns of morphology, immunophenotyping, genetics or gene expression signatures have been recognized in order to properly classify PTCL. Indeed, the etiopathogenesis and the physiological counterpart of the tumor cells are not well understood [1, 2, 6–9]. All these aspects make difficult to categorize the majority of PTCLs. Thus, whereas anaplastic large-cell lymphoma (ALCL), anaplastic lymphoma kinasa (ALK)-positive [10, 11] and angioimmunoblastic lymphoma (AILT) [12, 13] are well-defined entities, the most prevalent form, the so-called peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), is a highly *Correspondence to: Dr A. Lo´pez-Guillermo, Department of Hematology, Hospital Clı´nic, Villarroel 170, 08036 Barcelona, Spain. Tel: +34-932275475; Fax: +34-932275484; E-mail: [email protected]
heterogeneous group of aggressive T-cell lymphoma without a particular clinico-biological profile [14, 15]. It has been noted that the outcome of PTCLs is worse than that of aggressive B-cell lymphomas. In addition, patients with PTCL could not benefit, at least for the moment, of the immunochemotherapy that is the most important advance in the treatment of lymphomas during the last decade. Nevertheless, although the outcome of patients with PTCL is overall dismal, a small proportion of patients with PTCL might respond and even be cured with conventional chemotherapy [5, 16, 17]. Prognostic factors for response and survival in PTCL have been described in numerous studies. More interestingly, a number of prognostic scores have been applied or specifically built up for patients with PTCL. Thus, the International Prognostic Index (IPI) was built up in a large series of aggressive lymphomas, including PTCLs, and works nicely in both B-cell and T-cell neoplasms [18, 19]. However, the usefulness of IPI has been questioned in some studies in which IPI was not able to retain prognostic interest in multivariate analysis [20, 21]. More recently, the Prognostic Index for T-cell lymphoma (PIT) was developed by the ‘Intergruppo Italiano
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
[anaplastic large-cell lymphoma (ALCL) 21, PTCL not otherwise specified 56 and other 44)]. Complete response (CR) rate and 5-year overall survival (OS) were 41% and 31%, respectively. International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), International peripheral T-cell lymphoma Project score (IPTCLP) and modified Prognostic Index for T-cell lymphoma (mPIT) were calculated as in the original references. mPIT was only assembled to 41 patients in whom Ki-67 immunostaining was available. ALCL patients were analyzed separately. Results: Concordance among IPI, PIT and IPTCLP was 52% for low-risk group, 27% for low/intermediate-risk group, 20% for high/intermediate-risk group and 14% for high-risk group. IPI, PIT and IPTCLP predicted CR, with IPI being the best score in logistic regression. Neither Ki-67 immunostaining nor mPIT predicted CR. Five-year OS (low-risk versus intermediate- or high-risk categories) according to IPI, PIT, IPTCLP and mPIT were 52% versus 45%, 75% versus 49%, 58% versus 20% and 39% versus 0%, respectively. IPTCLP was the best score for OS in multivariate analysis. Conclusion: All the scores demonstrated their usefulness to assess the outcome of patients with PTCL, with IPTCLP being the most significant to predict OS. Key words: peripheral T-cell lymphoma, prognostic score, outcome
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Patients and methods: One hundred twenty-one patients (77 male/36 female, median age 53 years) with PTCL
original article
patients and methods patients One hundred twenty-one patients consecutively diagnosed with PTCL according to the World Health Organization (WHO) classification, from March 1990 to October 2008, and followed up in a single institution were selected for the present study. Most patients, but three (black African, Indian and Hispanic South American) were Spaniard with Caucasian origin. The distribution according to the histology subtypes was as follows: PTCL-NOS 56 (47%), ALK-positive ALCL 21 (17%), AITL 19 (16%), extranodal natural killer (NK)/T-cell lymphoma nasal type 15 (12%), hepatosplenic T-cell lymphoma (HSTL) 7 (6%) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) 3 (2%). Patients with ALK-positive ALCL were analyzed separately because of its particular behavior. Thus, the remaining 100 patients constituted the subjects of the present study. Staging maneuvers included patient history and physical examination (including Waldeyer’s ring area), blood cell counts and serum biochemistry, including LDH and b2-microglobulin (b2-m) levels, computerized tomography scan of chest, abdomen and pelvis, as well as BM biopsy. Post-therapy restaging consisted of the repetition of the previously observed test and/or biopsies. Response was assessed according to conventional criteria. Main initial characteristics of the patients, excluding ALK-positive ALCL, are listed in Table 1. Median age of the patients was 55 years (range 17–84 years) and the male/female distribution was 64/36. Performance status [Eastern Cooperative Oncology Group (ECOG)] more than one was observed in 40 cases (40%), advanced stage (Ann Arbor III or IV) in 81 cases (81%), any extranodal involvement in 76 cases (76%), including BM infiltration in 39 cases (39%), high serum lactic acid dehydrogenase (LDH) levels in 56 cases (56%) and platelet count <150 · 109/l in 28 cases (28%), and 56 (72%) patients of 78 with available data had high b2-m levels. Ninety-one (91%) patients were treated with adriamycin-containing chemotherapy, including 21 (21%) patients who received high dose of chemotherapy followed by stem cell transplantation as part of the first-line therapy. Response to treatment was as follows: CR was 36 cases (36%), partial response was 20 (20%) and failure to therapy was 44 (44%). Median follow-up was 3.9 years (range 2.8–5 years) for surviving patients. Five-year progression-free survival (PFS) of the series was 10% [95% confidence interval (CI) 4% to 16%] (Figure 1). Seventy-six patients had died during
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Table 1. Main features of 100 patients with PTCL at diagnosis (ALCL, ALK+ excluded) N
100
Age Median (range) £60 years Gender, n (%) Female Male, n (%) Histology, n (%) PTCL-NOS AILT NK/T-cell lymphomas HSTL SPTCL Ki-67 >75%a, n (%) Poor performance status (ECOG >1), n (%) B symptoms, n (%) Extranodal involvement ‡2 sites, n (%) Bone marrow involvement, n (%) Ann Arbor stage III–IV, n (%) High serum LDH, n (%) High serum b2-mb, n (%) Platelet cell count <150 · 109/l, n (%) First-line treatment, n (%)
55 (17–84) 63 (63) 36 (36) 64 (64) 56 19 15 7 3 8 40
(56) (19) (15) (7) (3) (20) (40)
52 (52) 37 (37) 39 81 56 56 28
(39) (81) (56) (72) (28)
9 (9) 91 (91) 36 (36) 20 (20) 44 (44)
a
Ki-67 count was available in 41 cases. b2-m levels was available in 78 cases. b2-m, b2-microglobulin; AILT, angioimmunoblastic lymphoma; ALCL, anaplastic large-cell lymphoma; CHOP, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone; ECOG, Eastern Cooperative Oncology Group; HSTL, hepatosplenic T-cell lymphoma; LDH, lactate dehydrogenase; NK, natural killer; PTCL, peripheral T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; SPTCL, subcutaneous panniculitis-like T-cell lymphoma. b
the follow-up, with a 5-year overall survival (OS) of 25% (95% CI 17% to 33%) (Figure 1). Five-year OS according to the histological subtypes was the following: ALK-positive ALCL, 55%; PTCL-NOS, 37%; AILT, 6% and 0% for extranodal NK/T-cell lymphoma nasal type, HSTL and SPTCL. As expected, 5-year OS of ALK-positive ALCL, was significantly high than that of the remainder PTCL (55% versus 25%, P = 0.003). The main initial and evolutive variables, including the histological parameters below indicated, were recorded and analyzed for prognosis.
histologic features The diagnosis of PTCL was based in all the cases on the criteria established in the WHO classification [1]. All the histologic slides were reviewed by at least two of different observers (AM, LC, AG-H and EC). Immunohistochemical stainings were carried out in all cases on paraffinembedded tissues, and the panel of monoclonal antibodies included antibodies against the following antigens: CD2, CD3, CD4, CD5, CD7, CD8,
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Linfomi’ for patients with PTCL-NOS based on age, performance status, serum lactate dehydrogenase (LDH) levels and bone marrow (BM) involvement [20]. This index was modified by the same group [modified Prognostic Index for T-cell lymphoma (mPIT)] changing BM involvement by the proliferation index as assessed by Ki-67 immunostaining [21]. PIT model might have superior capacity to predict the outcome in comparison with IPI, although this fact has not been completely confirmed [21–23]. The newest score was presented by the International peripheral T-cell lymphoma Project (IPTCLP) in the group of patients with PTCL-NOS and AITL [23] and takes into consideration age, performance status and platelet count as main variables. The four scores are able to predict the outcome of PTCL patients, but a comparative study of all the models in a homogeneous series of patients have never been addressed before. In this setting, the aim of the present study was to analyze the main clinico-biological features and outcome of patients with PTCLs from a single institution and to apply the above-mentioned indexes in order to systematically compare their predictive importance.
Annals of Oncology
original article
Annals of Oncology
Table 2. Variables used to calculate the different prognostic scores
Age (£60 versus >60) ECOG (£1 versus >1) LDH (normal versus high) Ann Arbor stage (I–II versus III–IV) Extranodal involvement (<2 versus ‡2 sites) BM involvement (negative versus positive) Platelet cell count (£150 versus >150 · 109/l) Ki-67 (%) (£75 versus >75) Figure 1. Overall survival (OS) and progression-free survival (PFS) of 100 patients with peripheral T-cell lymphoma (anaplastic large-cell lymphoma, ALK+ excluded).
prognostic scores in PTCL The following scores, previously described, were applied to the present series: IPI, PIT, IPTCLP and mPIT. The IPI was calculated according to the International Non-Hodgkin’s Lymphoma Prognostic Factors Project [18]. The variables used were age (£60 versus >60), performance status ECOG (£1 versus >2), LDH level (low versus high), Ann Arbor stage (I–II versus III–IV) and extranodal involvement (£1 versus >2). Four risk groups were defined by IPI: score 0–1, low risk; score 2, low-intermediate risk; score 3, high-intermediate risk and score 4–5, high risk. The PIT score was calculated as detailed by the ‘Intergruppo Italiano Linfomi’ [20]. Four variables were used to build up this score: age (£60 versus >60), performance status (ECOG £1 versus >2), LDH level (low versus high) and BM involvement (negative versus positive). Depending on the number of adverse prognostic factors (0, 1, 2 or ‡3), patients were classified into low-, low-intermediate-, high-intermediate- or high-risk groups, respectively. The IPTCLP score was calculated as detailed by the International PTCL Clinical and Pathology Review Project [23]. Three variables were used to construct this score: age (£60 versus >60), performance status (ECOG £1 versus >2) and platelet cell count (<150 · 109/l versus ‡150 · 109/l). Depending on the number of adverse prognostic factors (0, 1, 2 or 3), patients were classified into low-risk, low-intermediate-risk, high-intermediate-risk or high-risk groups, respectively. The mPIT score was calculated as detailed by the ‘Intergruppo Italiano Linfomi’ [21]. Four variables were used to constructed this score, three of them also being included in PIT (age, ECOG and LDH level) and Ki-67 immunostaining (<75% versus ‡75%). Depending on the number of adverse prognostic factors (0–1, 2 or ‡3), patients were classified into low-, intermediate- or high-risk groups, respectively. IPI, PIT and IPTCLP scores were assessed in all the cases, whereas mPIT was only assembled to 41 patients in whom Ki-67 immunostaining was available. No differences were observed in terms of response, PFS or OS
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PITb
IPTCLPc
mPITd
X X X X
X X X
X X
X X X
X X X X
Group risk were defined: a Four groups: 0–1, low; 2, low-intermediate; 3, high-intermediate and 4–5, high. b Four groups: 1, low; 2, low-intermediate; 3, high-intermediate and 3–4, high. c Four groups: 0, low; 1, low-intermediate; 2, high-intermediate and 3, high. d Three groups: 0–1, low; 2, intermediate and 3–4, high. BM, bone marrow; IPI, International Prognostic Index; ECOG, Eastern Cooperative Oncology Group; IPTCLP, International peripheral T-cell lymphoma Project; LDH, lactate dehydrogenase; mPIT, modified Prognostic Index for T-cell lymphoma. between patients with mPIT assembled and those in whom this score was not available. A summary of the variables used in the different scores is showed in Table 2.
statistical analysis Categorical data were compared using Fisher’s exact test and two-sided P value, whereas for ordinal data, nonparametric tests were used. The multivariate analysis of the variables predicting response was carried out by using a logistic regression. The definitions of CR, PFS and OS were the standard [24]. The actuarial survival analysis was carried out according to the method described by Kaplan and Meier [25] and the curves compared by the log-rank test [26]. The multivariate analysis for survival was carried out by using the stepwise proportional hazards model (Cox) [27].
results distribution according to the PTCL scores The distribution of the patients according to the risk group after applying the different scores is detailed in Table 3. The PIT score allocated a minor proportion of patients 16 (16%) in the low-risk group. The IPI, PIT and IPTCLP score had a similar proportion of the patients in the intermediate risk group 57 (57%), 62 (62%) and 64 (64%) respectively. At the high-risk group, the IPTCLP score allocated a minor number of cases 7 (7%). Regarding the modified PIT, this score showed a particular distribution with a majority proportion (56%) of the patients in low-risk group. Overall concordance among the three scoring systems (IPI, PIT and PTCLP) was 27%. Twentyseven patients were allocated to the same risk group with all the indexes. Total concordance in the three scores was 52% for low-risk, 27% for low/intermediate-risk, 20% for high/ intermediate-risk and 14% for high-risk groups.
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CD16, CD56, CD57, g-B, PF, bF-1/T-cell receptor (TCR)-b, TCR-d1 and BCL-2. Proliferation index was assessed by means of Ki-67 immunostaining and was evaluated in a semiquantitative manner after the observers studied the whole immunostained slide, scoring at least 200 cells in well-preserved areas. Samples were stratified into five groups: 1 (0% to <10% of the tumor cells were stained), 2 (10%–25%), 3 (25%–50%), 4 (50%–75%) and 5 (>75% positive cells). The cut-off used for prognostic issues and to build up the mPIT was 75%, similar to that originally described [21].
IPIa
original article
Annals of Oncology
Table 3. CR, PFS and OS according to the different prognostic scores and its distribution (ALCL, ALK+ excluded) N (%)
CR rate (%)
5-year PFS (%)
5-year OS (%)
Whole group IPI Low risk Low-intermediate risk High-intermediate risk High risk PIT Low risk Low-intermediate risk High-intermediate risk High risk IPTCLP Low risk Low-intermediate risk High-intermediate risk High risk mPITa Low risk Intermediate risk High risk
100 (100)
36
10
25
21 27 30 22
(21) (27) (30) (22)
36 33 17 14
24 15 0 0
52 25 20 0
16 27 36 22
(16) (27) (36) (22)
25 31 33 11
29 13 4 0
75 30 19 0
29 44 20 7
(29) (44) (20) (7)
31 52 14 3
23 6 0 0
58 15 5 0
24 (58) 8 (20) 9 (22)
57 7 36
10 0 0
39 0 0
a
mPIT was available in 41 cases. ALCL, anaplastic large-cell lymphoma; CR, complete response; IPI, International Prognostic Index; IPTCLP, International peripheral T-cell lymphoma Project; mPIT, modified Prognostic Index for T-cell lymphoma; OS, overall survival; PFS, progression-free survival.
response to treatment As previously indicated, CR rate of the series was 36%. Variables predicting for CR achievement were absence of B symptoms, ECOG <2 and platelet count >150 · 109/l. No difference was found in CR rate between patients who received or not adriamycin-containing chemotherapy. In addition, Ki-67 immunostaining was not able to significantly predict CR. Moreover, mPIT was not able to predict response to therapy in the 41 patients with this information available. IPI (P = 0.008), PIT (P = 0.03) and IPTCLP (P = 0.0001) scores predicted CR achievement, as detailed in Table 3. In Table 4, the same information is listed restricted to patients £65 years. A logistic regression analysis was carried out , including the three scores [IPI (low versus intermediate/high), PIT (low versus intermediate/high) and IPTCLP (low versus intermediate/ high)]. In the final model with 100 cases, IPI was the only score with capacity to predict CR achievement [relative risk (RR) = 2.45 (95% CI 1.27–3.63), P = 0.05]. progression-free survival Eighty-seven of 100 patients eventually progressed, including 24 of the 36 patients who had reached a CR. The 5-year PFS was 10% (95% CI 4% to 16%). Variables predicting poor PFS were presence of B symptoms, poor performance status (ECOG ‡2), platelet count <150 · 109/l and high serum LDH levels. IPI (P = 0.001), PIT (P = 0.001), PTCLP (P = 0.001) and mPIT (P = 0.05) also significantly predicted PFS, as detailed in Table 3 and
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Prognostic scores
N (%)
CR rate (%)
5-year PFS (%)
5-year OS (%)
Whole group IPI Low risk Low-intermediate risk High-intermediate risk High risk PIT Low risk Low-intermediate risk High-intermediate risk High risk IPTCL Low risk Low-intermediate risk High-intermediate risk High risk mPITa Low risk Intermediate risk High risk
74 (100)
39
14
30
19 22 20 13
(26) (30) (27) (17)
38 38 14 10
32 16 0 0
58 29 22 0
16 23 23 12
(22) (31) (31) (16)
31 34 28 7
29 15 10 0
75 30 15 0
29 32 11 2
(39) (43) (15) (3)
38 52 7 3
23 9 0 0
58 15 5 0
23 (80) 3 (20) 3 (20)
78 0 22
10 0 0
41 0 0
a
mPIT was available in 29 cases. ALCL, anaplastic large-cell lymphoma; CR, complete response; IPI, International Prognostic Index; mPIT, modified Prognostic Index for T-cell lymphoma; OS, overall survival; PFS, progression-free survival.
plotted in Figure 2. In Table 4, the same results are indicated for patients £65 years. A multivariate analysis was carried out including IPI, PIT and IPTCLP scores. In the final model with 100 cases, PIT was the most important variable to predict PFS [RR = 0.43 (95% CI 0.23–0.82), P = 0.01].
overall survival Seventeen (17%) patients died within 4 months from diagnosis and were considered as early death. Patients with intermediate or high-risk IPI, PIT, IPTCLP or mPIT had higher probability of early death than those with low-risk score (IPI: 82% versus 12%, P = 0.16; PIT: 100% versus 0%, P = 0.04; IPTCLP: 100% versus 0%, P = 0.004 or mPIT: 71% versus 29%, P = 0.07, respectively). Overall, 75 patients died during the follow-up, with a 5-year OS of 25% (95% CI 17% to 33). Unfavorable variables predicting OS were age >60 years, presence of B symptoms, poor performance status (ECOG ‡2), advanced Ann Arbor stage (III–IV), thrombocytopenia (platelet count <150 · 109/l), high serum LDH levels and high serum b2-m level. Ki-67 immunostaining and adriamycin-containing chemotherapy did not reach significance value predicting OS. IPI, PIT, IPTCLP and mPIT showed high value to predict OS, as detailed in Table 3 and plotted in Figure 3. In Table 4, the same data are detailed restricted to patients £65 years. A multivariate analysis was carried out including IPI (low versus intermediate/high), PIT (low versus intermediate/high) and IPTCLP (low versus
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Prognostic scores
Table 4. CR, PFS and OS according to the different prognostic scores and its distribution in patients with age £65 years (ALCL, ALK+ excluded)
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Annals of Oncology
intermediate/high). In the final model with 100 cases, IPTCLP was the most important variable to predict OS [RR = 3.52 (95% CI 2.01–7.12), P = 0.0001]. The same analysis was carried out only in the 56 patients diagnosed with PTCL-NOS, with IPTCLP maintaining the prognostic interest in this subset [RR = 7.69 (95% CI 2.21–13.17), P = 0.002].
PTCL scores in ALCL The different scores were applied to the 21 patients with ALKpositive ALCL. CR rate according to different scores was IPI (low-risk versus intermediate/high-risk group) 79% versus 21%, PIT (low-risk versus intermediate/high-risk group) 65% versus 35%, PTCLP (low-risk versus intermediate/high-risk group) 86% versus 14% (low-risk versus intermediate/high-risk group) and mPIT (low-risk versus intermediate/high-risk group) 100% versus 0%. Five-year OS of ALCL patients was 55% (95% CI 35% to 55%). PTCLP was the most important prognostic score for PFS. The four indexes (low-risk group versus intermediate/high-risk groups) also had a high value to predict OS: IPI, 90% versus 20% (P = 0.001); PIT, 100% versus
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20% (P = 0.001); PTCLP, 92% versus 11% (P = 0.0001) and mPIT, 100% versus 0% (P = 0.002).
discussion The outcome of the patients with PTCL, after excluding cutaneous forms and ALCL, is overall dismal. Thus, whereas during the last decade the introduction of immunochemotherapy has resulted in a dramatic improvement of the prognosis of aggressive B-cell lymphomas [28–30], no substantial advance was observed in patients with PTCL[31]. Since the results with chemotherapy are uniformly poor, more intensive treatments have been assayed, including autologous and allogeneic stem cell transplantation in order to improve these figures [32–37]. However, although experimental approaches might be useful in a selected subset of younger patients, morbidity and mortality associated to these procedures are still high. Therefore, the selection of high-risk patients is of paramount importance in this setting. Moreover, in all the PTCL series, there is a small proportion of patients who can survive for long periods of time or even be cured with
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Figure 2. Progression-free survival of the patients with peripheral T-cell lymphoma (anaplastic large-cell lymphoma, ALK+ excluded) according to the different scores: (A) International Prognostic Index (IPI), P = 0.001; (B) International peripheral T-cell lymphoma Project score (IPTCLP), P = 0.001; (C) PIT, P = 0.001 and (D) modified Prognostic Index for T-cell lymphoma (mPIT), P = 0.05. Four risk groups for IPI, IPTCLP and PIT scores: low risk (L), low/intermediate risk (L/I), high/intermediate risk (H/I) and high risk (H). Three risk groups for mPIT score: low (L), intermediate (I) and high (H).
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chemotherapy [16, 17, 23]. The identification of this group of potentially curable patients is also needed. Several studies have been addressed to identify prognostic factors in patients with PTCL [11, 13, 20, 21, 38, 39]. Regarding prognostic score systems, IPI was initially designed for its use in aggressive lymphomas, including T-cell lymphomas. IPI is easy to apply in the clinical practice and seemed useful to separate prognostic groups in PTCLs. However, the real value of IPI has been questioned in other PTCL series [4, 20–23, 40]. For this reason, several authors have proposed different prognostic scores, including IPTCLP, PIT and mPIT, to be used specifically in patients diagnosed with PTCL or even in specific histologic subtypes. Nevertheless, as it can be seen in Table 2, the parameters chosen to build up these scores are essentially the same. All four scores are based in clinical variables, with the mPIT being the only one that takes into consideration a biological parameter, the proliferation as assessed by Ki-67 immunostaining. The aim of the present study was to compare the usefulness of the four scores in predicting response with therapy, PFS and OS. No dramatic differences were observed among the indices, although in the multivariate analysis IPTCL showed to be somehow better than the others to predict OS.
402 | Gutie´rrez-Garcı´a et al.
The mPIT was assessed in only one-half of the patients in whom Ki-67 immunostaining was available, with this preventing its comparison with the other scores. Nevertheless, Ki-67 immunostaining was not able to predict response to therapy and its ability to predict OS was scarce in the present series. This is of note because the prognostic role of proliferation has been recently suggested in two different studies [11, 13, 21]. The relatively small number of cases and the histologic selection could explain this discrepancy. The four scores in this article analyzed divided PTCL patients in three or four prognostic categories. However, as it can be observed in Figures 2 and 3, the low-risk group, whatever the score used, emerged as a category clearly separated from the others. This is in agreement with the original papers [20, 21, 23] and it is clinically relevant. Of note, the low-risk group included the vast majority of long survivors. Nevertheless, young patients of any of the intermediate- or high-risk categories are probably candidates to experimental and/or intensive treatments. Whether or not the approach to low-risk patients could be more conservative is a subject of discussion. In fact, at the light of the present results, even these low-risk patients most likely will relapse.
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Figure 3. Overall survival of the patients with peripheral T-cell lymphoma (anaplastic large-cell lymphoma, ALK+ excluded) according to the different scores: (A) International Prognostic Index (IPI), P < 0.0001; (B) International peripheral T-cell lymphoma Project score (IPTCLP), P < 0.0001; (C) PIT, P < 0.0001 and (D) modified Prognostic Index for T-cell lymphoma (mPIT), P = 0.005. Four risk groups for IPI, IPTCLP and PIT scores: low risk (L), low/ intermediate risk (L/I), high/intermediate risk (H/I) and high risk (H). Three risk groups for mPIT score: low (L), intermediate (I) and high (H).
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Annals of Oncology
funding Spanish Ministry of Health and ‘Red Tema´tica de Investigacio´n Cooperativa en Ca´ncer’ (FIS-IP07/0409); Instituto de Salud Carlos III (RD06/0020/0051).
disclosure None of the authors declare conflicts of interest.
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references 1. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer 2008. 2. Ascani S, Zinzani PL, Gherlinzoni F et al. Peripheral T-cell lymphomas. Clinicopathologic study of 168 cases diagnosed according to the R.E.A.L. classification. Ann Oncol 1997; 8: 583–592. 3. Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the nonHodgkin’s lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 1998; 9: 717–720. 4. Au WY, Ma SY, Chim CS et al. Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years. Ann Oncol 2005; 16: 206–214. 5. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124–4130. 6. Lopez-Guillermo A, Cid J, Salar A et al. Peripheral T-cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. classification. Ann Oncol 1998; 9: 849–855. 7. O’Leary H, Savage KJ. The spectrum of peripheral T-cell lymphomas. Curr Opin Hematol 2009; 16: 292–298. 8. de Leval L, Bisig B, Thielen C et al. Molecular classification of T-cell lymphomas. Crit Rev Oncol Hematol 2009; 72: 125–143. 9. Rodriguez J, Gutierrez A, Martinez-Delgado B, Perez-Manga G. Current and future aggressive peripheral T-cell lymphoma treatment paradigms, biological features and therapeutic molecular targets. Crit Rev Oncol Hematol 2009; 71: 181–198. 10. Fornari A, Piva R, Chiarle R et al. Anaplastic large cell lymphoma: one or more entities among T-cell lymphoma? Hematol Oncol 2009; 27: 161–170. 11. Piva R, Agnelli L, Pellegrino E et al. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. J Clin Oncol 2010; 28: 1583–1590. 12. Dunleavy K, Davis RE, Landgren O et al. BCL-6 and rituximab in diffuse large B-cell lymphoma: where are we? Blood 2007; 109: 843–844; discussion 844–845. 13. Iqbal J, Weisenburger DD, Greiner TC et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 2010; 115: 1026–1036. 14. Agostinelli C, Piccaluga PP, Went P et al. Peripheral T cell lymphoma, not otherwise specified: the stuff of genes, dreams and therapies. J Clin Pathol 2008; 61: 1160–1167. 15. Rodriguez-Abreu D, Filho VB, Zucca E. Peripheral T-cell lymphomas, unspecified (or not otherwise specified): a review. Hematol Oncol 2008; 26: 8–20. 16. Savage KJ. Peripheral T-cell lymphomas. Blood Rev 2007; 21: 201–216. 17. Rudiger T, Weisenburger DD, Anderson JR et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 2002; 13: 140–149. 18. The International Non-Hodgkin’s Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–994. 19. Gisselbrecht C, Gaulard P, Lepage E et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin’s lymphomas. Groupe d’Etudes des Lymphomes de l’Adulte (GELA). Blood 1998; 92: 76–82. 20. Gallamini A, Stelitano C, Calvi R et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004; 103: 2474–2479. 21. Went P, Agostinelli C, Gallamini A et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006; 24: 2472–2479. 22. Lee Y, Uhm JE, Lee HY et al. Clinical features and prognostic factors of patients with ‘‘peripheral T cell lymphoma, unspecified’’. Ann Hematol 2009; 88: 111–119.
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In this study, as in others of the literature, we have considered patients with PTCL as a whole, with only ALCL being separately analyzed. However, this is not entirely correct because the definition of PTCL integrates >15 different categories in the WHO classification. These categories, although sharing a common T-cell origin and an aggressive behavior with poor outcome, have particular clinico-biological personality [1]. Some attempts to define specific scores for particular histological categories have been published (NK/ T-cell nasal type, ATLL and PTCL-NOS, etc.) [20, 21, 41, 42]. All the scores worked well in the PTCL-NOS, the largest group within PTCLs. The number of patients in other histological categories was too small to raise any conclusion. Finally, it is of note that in the group of patients with ALCL, all the scores were useful to define prognosis as well. The treatment given to our patients was quite homogeneous: >90% of them received adriamycin-containing regimens, in most cases combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Indeed, 20% of selected young patients were treated with intensive therapy. All the prognostic scores worked in the subpopulation treated with CHOP (data not shown). The influence of therapy on the prognostic factors of the patients is a well-known fact. Thus, the use of more effective treatments in PTCL, including new drugs, allogeneic stem cell transplantation or biological response modifiers, could result in an improvement of the outcome of the patients, as well as in a change of the variables predicting response and survival. Therefore, the usefulness of the PTCL scores in patients receiving new therapeutic approaches has to be demonstrated in future studies. The knowledge of PTCLs has considerably improved in recent years, thanks in part to the gene expression profile studies [11, 13, 38, 39]. Besides the diagnostic and etiopathogenic importance, these biological features probably have prognostic and therapeutic interest. For instance, gene expression profile allows to distinguish differentiate prognostic molecular subsets in AILT: a poor-prognosis group with two gene signatures associated with immunosuppressive functions and proliferative signals and a good-prognosis group with transcripts that have inhibitory effects on myeloid cell functions, associated with B cells or encode members of the ribosomal protein synthesis pathway. Hopefully, in the next future, some of the biological data could improve the predictive capacity of current scores [13]. In conclusion, all the four scores analyzed demonstrated their usefulness in predicting response and survival in patients with PTCL, although IPTCLP was the most significant to predict OS.
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34. 35.
36.
37. 38.
39.
40.
41.
42.
analysis by the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Ann Oncol 2004; 15: 1790–1797. Jantunen E, D’Amore F. Stem cell transplantation for peripheral T-cell lymphomas. Leuk Lymphoma 2004; 45: 441–446. Corradini P, Tarella C, Zallio F et al. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia 2006; 20: 1533–1538. Smith SD, Bolwell BJ, Rybicki LA et al. Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen. Bone Marrow Transplant 2007; 40: 239–243. Paolo C, Lucia F, Anna D. Hematopoietic stem cell transplantation in peripheral T-cell lymphomas. Leuk Lymphoma 2007; 48: 1496–1501. Cuadros M, Dave SS, Jaffe ES et al. Identification of a proliferation signature related to survival in nodal peripheral T-cell lymphomas. J Clin Oncol 2007; 25: 3321–3329. Ballester B, Ramuz O, Gisselbrecht C et al. Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas. Oncogene 2006; 25: 1560–1570. Aviles A, Diaz NR, Neri N et al. Angiocentric nasal T/natural killer cell lymphoma: a single centre study of prognostic factors in 108 patients. Clin Lab Haematol 2000; 22: 215–220. Lee J, Park YH, Kim WS et al. Extranodal nasal type NK/T-cell lymphoma: elucidating clinical prognostic factors for risk-based stratification of therapy. Eur J Cancer 2005; 41: 1402–1408. Suzumiya J, Ohshima K, Tamura K et al. The International Prognostic Index predicts outcome in aggressive adult T-cell leukemia/lymphoma: analysis of 126 patients from the International Peripheral T-Cell Lymphoma Project. Ann Oncol 2009; 20: 715–721.
Volume 22 | No. 2 | February 2011
Downloaded from http://annonc.oxfordjournals.org/ at NERL on June 5, 2015
23. Vose J. International Peripheral T-cell Lymphoma (PTCL) Clinical and Pathology Review Project: poor outcome by prognostic indices and lack of efficacy with anthracyclines. Blood 2005; 106: 811a. 24. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–586. 25. Kaplan GL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. P 26. Peto R, Pike MC. Conservatism of the approximation (O-E)2/E in the logrank test for survival data or tumour incidence data. Biometrics 1973; 29: 759–784. 27. Cox DR. Regression models and life tables. J R Stat Assoc 1972; 34: 187–220. 28. Coiffier B. State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 2005; 23: 6387–6393. 29. Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117–4126. 30. Pfreundschuh M, Schubert J, Ziepert M et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9: 105–116. 31. Gisselbrecht C. Molecular signatures in T-cell lymphoma. Blood 2010; 115: 919–920. 32. Mercadal S, Briones J, Xicoy B et al. Intensive chemotherapy (high-dose CHOP/ ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 2008; 19: 958–963. 33. Mounier N, Gisselbrecht C, Briere J et al. All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: a matched-control
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