research paper
Incidence, risk factors and outcome of histological transformation in follicular lymphoma
Annarita Conconi,1,* Carlotta Ponzio,1 Chiara Lobetti-Bodoni,1,2 Maddalena Motta,1 Paola M.V. Rancoita,1,3 Anastasios Stathis,1 Alden A. Moccia,1 Luca Mazzucchelli,4 Francesco Bertoni,1 Michele Ghielmini,1 Franco Cavalli1 and Emanuele Zucca1 1
Oncology Institute of Southern Switzerland
(IOSI), Bellinzona, Switzerland, 2Division of Haematology, Department of Experimental Medicine and Oncology, Ospedale San Giovanni Battista, University of Torino, Torino, Italy, 3Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno-Lugano, Switzerland, 4Institute of Pathology, Locarno, Switzerland and *Present address: Division of Haematology, Department of Clinical and Experimental Medicine, Ospedale Maggiore della Carita`, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Summary Histological transformation (HT) into diffuse large B-cell lymphoma (DLBCL) was documented in 37 of the 281 (13%; 95% CI, 9–18) follicular lymphoma (FL) patients treated at our institute from 1979 to 2007. HT occurred at a median of 2·75 years from initial FL diagnosis and HT rate was 15% at 10 years and 26% at 14 years, with a plateau from that point onward. Patients with bulky or extranodal disease, or those diagnosed before 1990 had a significantly higher risk of HT. When initial treatment strategies were taken into account, a reduced HT risk was seen in the patients initially managed with a ‘watch and wait’ policy, while the risk appeared significantly increased in the small subset of 18 patients initially managed with rituximab plus chemotherapy (P = 0·0005). HT was associated with a significantly shorter cause-specific survival (P = 0·0002). Predictors of survival after HT were the Follicular Lymphoma International Prognostic Index at diagnosis, as well as age and performance status at the time of HT. Our data confirm the adverse clinical outcome of FL after HT. In keeping with previous isolated reports, our findings suggest that there is a subgroup of patients in whom HT may not occur.
Received 4 October 2011; accepted for publication 2 December 2011 Correspondence: Emanuele Zucca, Oncology
Keywords: follicular lymphoma, histological transformation, prognosis, rituximab, chemotherapy.
Institute of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland. E-mail:
[email protected] Presented in part at the 14th Annual Meeting of the European Haematology Association (EHA), June 2009, Berlin, Germany and at the joint 15th Congress of the European CanCer Organisation (ECCO 15) and 34th Congress of the European Society for Medical Oncology (ESMO 34), September 20–24, 2009 Berlin, Germany.
In Western countries follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype after diffuse large B-cell lymphoma (DLBCL) and comprises approximately one quarter of all cases (Armitage & Weisenburger, 1998). In historical series, the median survival of FL is around 10 years and the disease displays an indolent clinical course characterized by a continuous pattern of relapses despite the activity of most proposed treatments with no First published online 20 February 2012 doi: 10.1111/j.1365-2141.2012.09054.x
clear evidence of cure, with the possible exception of the few patients with very early-stage disease treated with radiotherapy and the even fewer reported to achieve a long term relapse-free survival following allogeneic transplantation. FL treatment strategies have changed over time due to the continuous development of novel therapeutic approaches (Rohatiner et al, 2001; Hiddemann et al, 2005; Horning, 2008; Feuerlein et al, 2009) and recent reports have indicated ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 188–196
Histological Transformation of Follicular Lymphoma a possible improvement of patient survival in the last decade, characterized by the extensive use of the anti-CD20 monoclonal antibody rituximab (Fisher et al, 2005; Swenson et al, 2005; Sacchi et al, 2007; Sebban et al, 2008; Conconi et al, 2010). Nevertheless, histological transformation (HT) to a more aggressive DLBCL remains a critical event in the natural history of FL, usually associated with refractoriness to treatment, rapid clinical progression and dismal outcome (Gine´ et al, 2006; Montoto et al, 2007; Al-Tourah et al, 2008; Montoto & Fitzgibbon, 2011) In most cases, it is clinically marked by rapidly growing adenopathy, B-symptoms and rising lactate dehydrogenase (LDH) levels. Because of the different definition criteria, biopsy policies and length of follow-up, the reported incidence of HT is widely variable, ranging from less than 15% to more than 60% in published series (Cullen et al, 1979; Hubbard et al, 1982; Acker et al, 1983; Horning & Rosenberg, 1984; Gallagher et al, 1986; Ersboll et al, 1989; Bastion et al, 1997; Gine´ et al, 2006; Montoto et al, 2007; Al-Tourah et al, 2008; De Jong & de Boer, 2009; Yuen et al, 1995). In recent years, several studies have addressed the pathogenetic mechanisms of HT (Davies et al, 2005, 2007; Rossi et al, 2006; Carlotti et al, 2009; Gentles et al, 2009; Johnson et al, 2009; Lawrie et al, 2009; O’Shea et al, 2009; Wrench et al, 2011), but very few reports have been published on the clinical features and prognostic factors (Gine´ et al, 2006; Montoto et al, 2007; Al-Tourah et al, 2008; Morley et al, 2008). The annual risk has been estimated at 3% and reported to remain steady during long follow-up (Gine´ et al, 2006; Montoto et al, 2007; Al-Tourah et al, 2008; Morley et al, 2008). Some reports seem to indicate that transformation may not necessarily represent the final event of the natural history of FL and there may be a subgroup of patients in whom it does not occur (Montoto et al, 2007; Al-Tourah et al, 2008) It remains still unclear whether the most modern therapeutic policies are affecting the risk and outcome of HT. The purpose of the present analysis was to assess the frequency and outcome of HT to DLBCL and to document the risk factors that may predict for it, in FL patients treated at the Oncology Institute of Southern Switzerland (IOSI). Given that the IOSI the unique cancer centre in Southern Switzerland, our study is likely to represent a population-based rather than a referral centre patient selection and may offer useful information.
Patients and methods The electronic database of NHL cases treated at the IOSI from 1979 to 2007 includes 281 patients whose diagnosis was revised as FL grade 1–3a according to the World Health Organization (WHO) classification (Harris et al, 2008). The database contains information concerning demographic, clinico-pathological and outcome data for each patient. ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 188–196
In the early 1990s retroactive manual data entry from patients’ charts was done. Since 1996, information regarding each new lymphoma patient was prospectively collected and a retrospective histological review was performed for all cases diagnosed before the adoption of the Revised EuropeanAmerican Lymphoma/WHO classification. Bone marrow biopsy was performed in all patients at diagnosis, and thereafter, when clinically required. At the time of clinical relapse or progression, a lymph node biopsy was made whenever feasible. In all reported cases of evolution into an aggressive histotype, the histopathology documentation was available and transformation was confirmed at histological review. HT was strictly defined by the presence of histological characteristics of DLBCL; neither the documentation of an increased proportion of large cells (i.e. progression from grade 1 and 2 to grade 3) nor the development of a diffuse pattern with persistence of follicular morphology were considered as transformation. For cases diagnosed before their adoption, both the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI), used to assess the risk of progression and death (Solal-Celigny et al, 2004; The International Non-Hodgkin’s Lymphoma Prognostic Factors Project, 1993) were, whenever possible, retrospectively assigned following the examination of patients’ records. Overall survival (OS), cause-specific survival (CSS) and progression-free survival (PFS) were defined according to the revised National Cancer Institute criteria (Cheson et al, 2007). Statistical analysis was conducted using the STATA Release 11 statistical software package (StataCorp 2009; College Station, TX, USA). Follow-up was calculated as the median time to censoring using a reverse Kaplan–Meier analysis (Altman et al, 1995). Survival probabilities were calculated using the life table method and survival curves were estimated by the method of Kaplan–Meier with upper and lower confidence bands calculated using Greenwood’s approximation; differences between curves were analysed using the logrank test (Bland & Altman, 2004). Either backward logistic regression or Cox proportional hazard model as appropriate, were used for multivariate analysis and estimation of the hazard ratio and its confidence interval. Binomial exact 95% confidence intervals (95% CI) were calculated for incidence percentages. Either the chi-squared test or the Fisher’s exact test was used for testing associations in two-way tables, as appropriate. P values of 0·05 or less (two-sided test) were considered to indicate statistical significance.
Results Patients’ population The median follow-up time for the whole cohort of patients was 10 years. The main clinical features at time of diagnosis 189
A. Conconi et al Table I. Clinical features of the whole cohort and of the 37 patients with biopsy-proven histological transformation (HT).
Patient characteristics Median age, years (range) Female sex ECOG PS > 1 B symptoms Bulky disease (max LN diameter > 7cm) Extranodal involvement Bone marrow involvement Ann Arbor stage I-II III-IV Histological grade 3 Elevated LDH (>normal upper value) Elevated b2M (>normal upper value) Poor risk FLIPI ( 3 risk factors)
All patients at diagnosis (N = 281) n (%)
HT subset at diagnosis (N = 37) n (%)
HT subset at the time of transformation (N = 37) n (%)
58 (21–92) 150 (53) 18 (6) 39 (14) 29 of 263 studied (11)
53 (22–81) 17 (46) 0 3 (8) 6 (18)
59 (23–84)
119 (42) 108 (38)
10 (27%) 10 (27)
22 (59) 10 (27)
92 189 28 44 of 189 studied 43 of 121 studied 48 of 173 studied
(33) (67) (10) (23) (36) (28)
14 23 4 6 of 23 studied 6 of 13 studied 4 of 20 studied
(38) (62) (11) (26) (46) (20)
4 (11) 4 (11) 5 (13)
11 of 27 studied (41) 16 of 27 studied (59) 7 of 23 studied (30) 4 of 13 studied (31) 8 of 23 studied (35)
HT, histological transformation; ECOG PS, Eastern Cooperative Oncology Group performance score; LN, lymph node; LDH, lactate dehydrogenase; b2M, b2 microglobulin; FLIPI, Follicular Lymphoma International Prognostic Index.
are summarized and compared to those at transformation in Table I.
Treatments Seventy-two asymptomatic patients (with no bone marrow failure or other vital organ impairment, no rapidly growing adenopathy and no compression symptoms) underwent an initial watchful waiting policy. In 39 patients (including 14 patients in whom the initial surgical biopsy removed the entire macroscopic tumour) this expectant management was never followed by any active treatment. Most patients received a chemotherapy programme as front-line treatment, in most cases a single alkylating agent or combination therapy not including anthracyclines. Doxorubicin-based regimens were delivered only to 60 patients. A minority received upfront anti-CD20 immunotherapy, either in combination with chemotherapy (18 patients) or alone (20 patients). The median OS for the entire group of 281 patients was 11 years (95% CI, 9–14 years), whilst the median CSS was not reached; a detailed analysis of the treatment outcome in the whole cohort has already been published (Conconi et al, 2010).
Incidence of histological transformation Histological transformation was diagnosed in 37 cases (13%, 95% CI, 9–18) at a median time from diagnosis of 2·75 years (interquartile range, 1·3–5 years). The transformation rate at 5, 10 and 15 years was 13% (95% CI, 9–18), 15% (95% CI, 11–21), 26% (95% CI, 18–37) respectively (Fig. 1A). Clinical features of patients at the time of HT are listed in Table I. 190
Univariate analysis of clinicopathological features associated with transformation Histological transformation was associated with age below 65 years at presentation and with initial involvement of extranodal sites other than bone marrow. HT rates at 5 and 15 years were 15% (95% CI, 11–22) and 26% (95% CI, 18– 37) respectively, for patients younger than 65 compared to 4% (95% CI, 1–11) and 32% (95% CI, 11–71) for the older patients (P = 0·024). Patients with extranodal involvement other than bone marrow showed 5- and 15-year HT rates of 29% (95% CI, 17–47) and 37% (95% CI, 21–60) respectively, in comparison with rates of 9% (95% CI, 6–14) and 24% (95% CI, 15–36) for those without involvement (P = 0·029). HT was also more frequent in patients diagnosed before 1990, with HT rates at 5 and 15 years of 9% (95% CI, 6–15) and 16% (95% CI, 9–25) respectively, compared to 20% (95% CI, 12–32) and 38% (95% CI, 25–55) for those diagnosed in the subsequent decades (P = 0·001). None of the other examined clinical variables at diagnosis (performance status according to Eastern Cooperative Oncology Group (ECOG) criteria, elevated serum LDH and beta2-microglobulin levels, increased erythrocyte sedimentation rate, advanced stage, bulky disease, bone marrow involvement, low albumin concentration, low haemoglobin level, histological grade, unfavourable IPI and FLIPI scores) was significantly associated with HT.
Multivariate analysis of risk factors for transformation After backward logistic regression including all the clinicopathological variables available in at least 90% of the patients ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 188–196
Histological Transformation of Follicular Lymphoma
(A)
(B)
(C)
(D)
Fig 1. Kaplan–Meier estimate of the cumulative incidence of histological transformation. (A) All patients in the cohort (n = 281). The grey area indicates the 95% confidence interval. (B) Risk of transformation by the presence of bulky disease at presentation. (C) Risk of transformation according to the presence of extranodal involvement other than bone marrow at diagnosis. (D) Risk of transformation according to the year of diagnosis.
(i.e. age at diagnosis 65 years, sex, stage 3, performance status > 1, bone marrow involvement, extranodal sites involvement other than bone marrow, B-symptoms, bulky disease, grade, year of diagnosis before 1990) only age below 65 years (P = 0·025; HR = 2·9; 95% CI, 1·1–7·3) and diagnosis before 1990 (P = 0·001; HR = 3·9; 95% CI, 1·6–6·9) remained significantly associated with HT. It should be noted, however, that patients diagnosed before 1990 had an extremely different median follow-up, in comparison with those diagnosed later (21 vs. 8 years, P < 0·0001).
Actuarial risk of transformation At univariate analysis (logrank test), the actuarial risk of HT was significantly higher in patients presenting with bulky disease (Fig. 1B, P = 0·0430) or with involvement of extranodal sites other than bone marrow (Fig. 1C, P = 0·0128) and in those diagnosed before 1990 (Fig. 1D, P = 0·0316). The cumulative rate of transformation at 10 and 15 years was 20% (95% CI, 12–32) and 38% (95% CI, 25–55%) respectively, for the subset of patients diagnosed before 1990 compared to 13% (95% CI, 8–21) and 15% (95% CI, 10–25) respectively, for those diagnosed during the subsequent decades. ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 188–196
Fig 2. Kaplan–Meier estimate of the cumulative incidence of histological transformation according to front-line treatment.
For 26 patients (70%, 95% CI, 53–84) transformation was the first event after the initial treatment. The median number of treatments given prior to transformation was 1 (range 1–6). Among the 37 patients who eventually had an HT, only 6 (16%) were initially managed with a watchful waiting policy 191
A. Conconi et al Table II. Percentages of FL patients with HT and with potential risk factors within the principal subgroups defined by the front-line treatment.
Risk factor HT (%) Grade 3 (%) ECOG PS = 0 (%) B symptoms (%) Stage IV (%) Poor FLIPI (%) Bulky disease (%) High LDH (%) Age > 65 years (%) Bone marrow involvement (%) Extranodal sites other than bone marrow (%) Diagnosis after 1990 (%)
Rituximab only (N = 20)
R-chemotherapy (N = 18)
Chemotherapy only (N = 204)
Watch & wait only (no treatment before HT) (N = 39)
P-value = = < = = = = = = = =
0 0 95 5 55 20 7 16 15 45 25
33 28 67 22 61 41 15 35 28 56 17
14 10 52 17 51 30 13 23 33 40 21
8 8 87 0 17 8 3 20 41 18 10
P P P P P P P P P P P
0·019 0·047 0·001 0·005 0·001 0·059 0·271 0·580 0·237 0·021 0·428
100
100
68
80
P < 0·001
HT, histological transformation; ECOG PS, Eastern Cooperative Oncology Group performance score; LDH, lactate dehydrogenase; FLIPI, Follicular Lymphoma International Prognostic Index.
(versus treatment at diagnosis). This initial expectant management was not associated with an increased risk of subsequent transformation. Patients first managed with a ‘watch and wait’ approach presented a reduced actuarial risk of HT, without statistical significance, in the whole study population (logrank test, P = 0·07), but this was significant for cases diagnosed after 1990 (logrank test, P = 0·0064). Use of doxorubicin did not affect the risk of transformation. Six HT (33%, 95% CI, 13–59) were recorded in the small subset of 18 patients initially managed with rituximab plus chemotherapy (R-chemotherapy), comprising 4 of 10 cases who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), 1 of the 2 treated with R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone) and 1 of the 6 treated with R-chlorambucil. The R-chemotherapy subset seemed to have a higher risk of HT
(A)
(Fig. 2), in comparison with 28 HT among 204 patients treated with chemotherapy (14%, 95% CI, 9–19) and three HT among 39 who received no treatment (8%, 95% CI, 2–21). No HT was detected in the subset of 20 patients (one-sided, 97·5% CI, 0–0·17) who had single-agent rituximab as frontline treatment. Notably, the patients who had front-line Rchemotherapy included a significantly increased portion of cases with histological grade 3 and with possibly adverse prognostic factors (Table II). At multivariate analysis (Cox regression considering diagnosis 60 years (P = 0·0244), ECOG performance score (PS) >1 (P = 0·0215), and elevated b2-microglobulin (P < 0·001). Age > 60 years (P = 0·010; HR = 3·35, 95% CI: 1·34–8·42) and ECOG PS > 1 (P = 0·007; HR = 5·17, 95% CI: 1·58–16·98) remained powerful predictors of outcome at multivariate analysis (b2-microglobulin was not included in the Cox model due to the high rate of missing observations).
Discussion
Fig 4. Kaplan–Meier estimate of overall survival following histological transformation in follicular lymphoma patients, with its 95% confidence interval indicated by the grey area.
CI, 1·3–5·7), bulky disease (P = 0·025; HR = 2·8; 95% CI, 1·1–7·1) and extranodal involvement other than bone marrow (P = 0·013; HR = 2·6; 95% CI, 1·2–5·4).
Outcome after transformation The rate of transformation reached a plateau after 14 years and remained at 26% from that point onward (Fig. 1A). Indeed, HT was not diagnosed in the 31 patients (of whom 13 have died) with a minimum follow-up of 14 years (median 17 years; range 14–29). Patients experiencing HT had a worse outcome than those with no documented transformation; long-term CSS (Fig. 3A) was significantly shorter (44% vs. 73% at 10 years, P = 0·0002). OS (Fig. 3B) was also shorter (36% vs. 55% at 10 years), but this difference did not reach statistical significance (P = 0·058). The survival patterns from FL diagnosis in patients with and without HT are summarized in Table III. The median survival after transformation was 2·7 years (interquartile range, 0·8–6·4 years). ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 188–196
HT is considered a common event in the natural history of FL, but the definition of transformed FL varies considerably among published series, being based on cytological features, histological samples, and, in some instances, also on purely clinical grounds (Montoto & Fitzgibbon, 2011). The diagnosis of HT in the present study was unequivocally based on a biopsy sample showing the presence of DLBCL, rather than relying on fine-needle aspiration or on clinical criteria. It may not always have been possible to obtain a biopsy (because of the poor clinical condition of the patient or because of lymphoma progression in not easily accessible areas), hence, this stringent approach may have resulted in some underestimation of the real incidence. Nevertheless, this approach results in the exclusion of those cases where the clinical aggressiveness is not accompanied by histological changes. Among the recent reports, the population-based study from British Columbia (including only patients younger than 60 years) indicated that the outcome of patients with transformation defined on clinical criteria (i.e. by the presence of any of the following conditions: increased LDH, B-symptoms, rapidly growing adenopathy, new extranodal sites or hypercalcaemia) was similar to that of histologicallydiagnosed cases. (Al-Tourah et al, 2008) On the other hand, the data from the biopsy-based series of the St Bartholomew’s Hospital showed that a relationship between clinical aggressiveness and HT cannot be taken as absolute because only a quarter of transformed cases had poor performance 193
194
HT, histological transformation; OS, overall survival; DLBCL, diffuse large B cell lymphoma; PS, performance score; LDH, lactate dehydrogenase; IPI, international prognostic index.
2·7 15% 26% 2·75 (1·3–5) 13% 10 Histology only DLBCL 281 Present series
58
1·7 30% 45% 3·3 (0·2–16) 28% 9 Clinical, cytology, histology DLBCL or Burkitt-like 48 600
3 (0·1–16·2) 27% 15 Histology only DLBCL 55 325
Al-Tourah et al (2008)
1·2
Limited stage, good PS, low IPI at the time of HT Number of previous relapses, timing of transformation, good PS and normal LDH at HT Limited disease at HT (single nodal region, non bulky, no B symptoms, no major extranodal involvement) Age < 60 years, good PS and normal b2-microglobulin at the time of HT 1·2
15% 22% 28% 37% 3·5 (0·6–20) 11% 6·5 Cytology, histology DLBCL 54 276
Prevalence HT definition Study
Gine´ et al (2006) Montoto et al (2007)
Median OS after HT (years) HT risk at 10 and at 15 years Median time to transformation (years, range) Median follow-up (years) Diagnostic method Median age (years) Number of patients
Table IV. Histological transformation patterns in the present study and in the other three series of follicular lymphomas published in the past decade.
Factors predicting longer OS after HT
A. Conconi et al status or two or more extranodal sites. (Montoto et al, 2007). The overall frequency and long-term probability of transformation (27% at 15 years) in the present study are similar to other recently reported series (Table IV) with some differences that are proabably due to variability of biopsy policies and follow-up duration (Bastion et al, 1997; Gine´ et al, 2006; Montoto et al, 2007; Al-Tourah et al, 2008). Our findings are also in keeping with other reports indicating a poorer clinical outcome after HT (Hubbard et al, 1982; Acker et al, 1983; Bastion et al, 1997; Gine´ et al, 2006; Montoto et al, 2007; Al-Tourah et al, 2008; Yuen et al, 1995). Notably, in our series, HT was not diagnosed in 31 patients (of whom 13 have died) with a minimum follow-up of 14 years (range 14–29; median, 17 years). In line with the finding of Montoto et al (2007), the risk of transformation seemed to decline drastically after 15 years, suggesting that there may be a subset of FL in whom HT does not take place. This hypothesis is supported by an earlier study from France, in which a plateau in the transformation risk was also seen, with the latest transformation occurring 10 years after diagnosis (Bastion et al, 1997). This observation might be explained by some recent molecular studies supporting the existence of distinct subtypes of FL with distinct oncogenic pathways of HT (Davies et al, 2007; Carlotti et al, 2009; Gentles et al, 2009). However, these data are still premature and, on the other hand, no plateau was observed for the risk of transformation in the population-based study from British Columbia, which showed a 3% annual risk that remained steady during follow-up beyond 15 years (Al-Tourah et al, 2008). This study, however, also included a relevant number (36% of the series) of transformations defined only on clinical grounds, whilst in our study and that of Montoto et al (2007) only histologically confirmed cases were considered. There is a huge variability in the literature concerning the clinicopathological features associated with increased transformation risk. In addition to different definition criteria, and re-biopsy policies at the time of progression, this variability can also depend on length of follow-up, sample size, amount of missing data, inclusion and extent of autopsy information. Here, factors that can predict for transformation were examined at univariate and multivariate analysis in our series. In contrast with the report from Montoto et al (2007), but in keeping with the data from Stanford University (Horning & Rosenberg, 1984) and from the French Groupe d’Etude des Lymphomes de l’Adulte (GELA) (Brice et al, 1997), our study did not find an increased risk of HT for the patients initially managed with a watchful waiting policy. It is difficult to ascertain whether the initial therapeutic approach has a direct impact on the risk of subsequent transformation. In our series, HT was more frequent in the group of patients diagnosed before 1990 compared to the subsequent period. This may not necessarily be due to therapeutic ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 188–196
Histological Transformation of Follicular Lymphoma changes (e.g. an earlier use of rituximab or anthracyclinecontaining regimens). Indeed, as transformation is a timedependent event, the length of follow-up is likely to have contributed to our finding. The higher transformation incidence seen in our study among patients receiving front-line R-chemotherapy (in comparison with those never treated or treated with chemotherapy only or rituximab only) should be taken very cautiously. The retrospective nature is an intrinsic limitation of this study and a selection bias is strongly suggested by the high proportion of patients with histological grade 3 and adverse prognostic factors among those initially treated with R-chemotherapy. Nevertheless, the potential impact of initial treatment on HT remains a relevant unanswered question and the literature data on this issue are limited and controversial (Montoto & Fitzgibbon, 2011). The retrospective study from British Columbia apparently suggested that a more efficient front-line treatment might reduce the HT risk, showing that the risk of HT is higher for patients receiving single agent therapy (either alkylators or purine analogs) in comparison with those treated with doxorubicin-based regimens (Al-Tourah et al, 2008). Differently from Al-Tourah et al (2008), but in keeping with a Spanish report (Gine´ et al, 2006), we did not detect a different HT incidence according to whether patients had received doxorubicin or not. In all these studies the decision to use doxorubicin-con-
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Acknowledgements This study has been partially supported by a grant from the Swiss Cancer League (Krebsliga Schweiz 01690-03-2005). We thank the precious contribution of Cristina Morinini and Elena Porro for the data management.
Authorship A Conconi and E Zucca: conception and design of the study, data analyisis and interpretation, and manuscript writing; C Ponzio and C Lobetti-Bodoni: contribution to study conception, collection and assembling of data, data analysis and interpretation, manuscript writing; M Motta, A Stathis, A Moccia: collection and assembling of data, manuscript writing; PMV Rancoita: statistical analyisis and interpretation; L Mazzucchelli: histopathology revisions, F Bertoni, M Ghielmini and F Cavalli: conception and design of the study, data analyisis and interpretation. Final approval of manuscript was given by all authors.
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