High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group

M. D. Caballero1,+, J. A. Pérez-Simón1, A. Iriondo2, J. J. Lahuerta3, J. Sierra4, J. Marín5, M. Gandarillas2, R. Arranz6, J. Zuazu7, V. Rubio8, A. Fernández de Sevilla9, E. Carreras10, J. García-Conde11, J. García-Laraña12, C. Grande13, A. Sureda14, M. J. Vidal5, J. Rifón15, C. Pérez-Equiza15, R. Varela16, J. M. Moraleda17, J. C. García Ruíz18, C. Albó19, R. Cabrera20, J. F. San Miguel1 and E. Conde On behalf of the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea Spanish Cooperative Group2

1 Hospital Clínico Universitario, Salamanca; 2 Hospital Marqués de Valdecilla, Santander; 3 Hospital 12 de Octubre, Madrid; 4 Hospital de la Santa Creu i Sant Pau, Barcelona; 5 Hospital Ntra. Sra. De Aránzazu, San Sebastián; 6 Hospital de la Princesa, Madrid; 7 Hospital de la Vall de Hebrón, Barcelona; 8 Hospital de Jerez, Jerez de la Frontera; 9 Institut Català d’Oncologia, Hospital Duran i Reynals, Barcelona; 10 Hospital Clinic i Provincial, Barcelona; 11 Hospital Clínico Universitario, Valencia; 12 Hospital Ramón y Cajal, Madrid; 13 Hospital 12 de Octubre, Madrid; 14 Hospital de la Santa Creu i Sant Pau, Barcelona; 15 Clínica Universitaria de Navarra, Pamplona; 16 Hospital Juan Canalejo, La Coruña; 17 Hospital General Universitario, Murcia; 18 Hospital de Cruces, Bilbao; 19 Hospital Xeral i Cies, Vigo; 20 Hospital Puerta de Hierro, Madrid, Spain

Received 5 March 2002; revised 11 June 2002; accepted 17 July 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The purpose of this study was to analyse the results and prognostic factors influencing overall survival (OS) and disease-free survival (DFS) in 452 patients diagnosed with diffuse large cell lymphomas (DLCL) treated with high-dose therapy (HDT) included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry.

Patients and methods:

At transplantation, median age was 42 years (range 15–73), 146 patients (32%) were transplanted in first complete remission (1st CR), 19% in second CR (2nd CR) and 47% had active disease: sensitive disease in 157 (35%) patients [95 were in first partial remission (1st PR) and 62 in second PR (2nd PR)] and refractory disease in 55 (12%) patients. Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 51 patients (12%). Conditioning regimen consisted of BEAM (carmustine, etoposide, cytarabine and melphalan) in 39% of patients, BEAC (carmustine, etoposide, cytarabine and cyclophosphamide) in 33%, CBV (carmustine, etoposide and cyclophosphamide) in 10% and cyclophosphamide plus total body irradiation (TBI) in 12%.

Results:

Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 53% and 43%, respectively. The transplant-related mortality was 11% (53 cases). By multivariate analysis three variables significantly influenced OS and DFS: number of protocols to reach 1st CR, disease status at transplant and TBI in the conditioning regimen. Age-adjusted IPI at transplantation also influenced OS.

Conclusions:

Prolonged OS and DFS can be achieved in patients with DLCL after HDT and our results suggest that the best line of chemotherapy should be used up-front in patients considered as candidates for HDT in order to obtain an early CR. Resistant patients are not good candidates for HDT and they should be offered newer strategies. Finally, polichemotherapy conditioning regimens offer better results compared with TBI.

Key words: autologous transplant, diffuse large cell lymphoma, high-dose therapy, prognostic factors


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Diffuse aggressive non-Hodgkin’s lymphoma (NHL) constitutes 50% of all NHLs. Prognosis has improved in the last decades and first-line chemotherapy regimens including anthracyclines induce complete remission (CR) in 60–80% of patients, although only 40% of these will be disease free in the long term [13]. Survival in diffuse large cell lymphoma (DLCL) is determined by clinical and biological prognostic factors. According to the International Prognostic Index (IPI), for a patient <60 years of age with an unfavourable prognostic index (IPI 2, 3) overall survival (OS) at 5 years is between 46% and 32% [4]. Thus, conventional combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) should not be considered an effective treatment for these patients, and even in patients categorised as ‘low risk’ according to the IPI index, CHOP results should be included.

In order to improve the results of standard treatments, high-dose chemotherapy (HDT) followed by autologous stem cell transplantation has been widely used in patients with DLCL [57]. This is the treatment of choice for patients in relapse with chemotherapy-sensitive disease, as has been confirmed by a randomised Parma study [8], in which patients in partial remission (PR) who received HDT had a significantly better event-free survival (EFS) and OS than those treated with chemotherapy (46% and 53% versus 12% and 32% for the HDT and chemotherapy groups, respectively). In contrast, the role of HDT in newly diagnosed patients has to be determined. Although several studies suggest a benefit of autologous transplantation for patients with poor prognostic factors [911], results in randomised trials using HDT as part of the initial treatment remains controversial. In this sense, whereas some studies show an advantage for transplanted patients [1215], other studies [1621] failed to show a benefit of HDT as compared with conventional treatment.

In order to identify those patients with large cell lymphoma who would benefit from HDT, we performed a retrospective analysis on a series of 452 patients included in the Spanish lymphoma registry [Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GEL/TAMO)].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 452 patients diagnosed with DLCL, according to the working formulation (WF), had been included in the GEL/TAMO registry and constitutes the body of this analysis.

Inclusion criteria were as follows: diagnosis of DLCL according to the working formulation [22] (diffuse mixed, diffuse large cell and immunoblastic lymphoma), age between 18 and 65 years, left ventricular ejection fraction >50%, forced expiratory volume in 1 s (FEV1) >50% and carbon monoxide diffusion capacity >50% of predicted.

Criteria for HDT in all institutions were relapsed lymphoma patients or failure to achieve remission after induction chemotherapy. In addition, patients in first CR (1st CR) were included if they were considered to have a high risk of relapse according to the presence of poor prognostic factors.

Response criteria
Complete remission (CR) was defined as complete tumour disappearance and partial remission (PR) as the reduction of measurable disease by >=50% without the appearance of any new lesions. Progressive disease was defined as unmodified disease after the transplant or the appearance of new lesions. Prior to transplantation complete re-staging, including evaluation of previously affected areas, was available in all patients. Response to the transplant was assessed 90 days after infusion. Patients who died within 100 days after transplantation were considered non-evaluable for response. Early procedure-related mortality was defined as death within 100 days after high-dose therapy not related to disease relapse or progression. Toxic mortality was considered at any time if it was related to a recognised complication of the procedure.

Patient characteristics at diagnosis
Patient characteristics at diagnosis are listed in Table 1. According to the WF, patients were diagnosed with diffuse mixed cell lymphoma (n = 72; 16%), diffuse large cell lymphoma (n = 289; 64%) and immunoblastic lymphoma (n = 91; 20%). At diagnosis, 41% of patients had a performance status of 2 to 4, 239 (53%) had bulky disease (>=10 cm) and 101 (22%) bone marrow involvement; 28% of patients had at least two extranodal disease localisations, 329 (73%) were stages III–IV and more than half (62%) had high lactate dehydrogenase (LDH) levels. High ß2 microglobulin levels were detected in 52% of cases and 61% of patients had an aged-adjusted IPI of 2 or 3.


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Table 1. Patient characteristics at diagnosis
 
Treatment characteristics and response to prior therapy
As first-line treatment (Table 1), 51% of patients received CHOP, 5% and 32% were treated with second and third generation regimens, respectively, and 7% received other different schemes. Response to this first-line treatment was as follows (Table 1): CR in 308 patients (68%), PR in 105 patients (23%) and stable disease or progressive disease in 38 patients (9%). The number of treatment lines prior to transplantation were one in 293 (65%), two in 141 (31%) and three in 17 (4%). Intervals between diagnosis to first CR, diagnosis to transplantation and last CR to transplantation were 5, 11 and 3 months, respectively.

Patient characteristics at transplant
Patient characteristics at transplant are listed in Table 2: median age was 42 years (range 13–73), 146 patients (32%) were transplanted in 1st CR and 19% in >=2nd CR. Almost half of the patients (47%) had active disease at transplant: sensitive disease in 157 (35%) patients (95 were in 1st PR and 62 in 2nd PR) and refractory disease in 55 (12%) patients. A performance status of 2 to 4 was observed in 6% of patients and another 6% had bulky disease; 4% had bone marrow involvement and 5% had two or more extranodal sites involved. 101 of 212 patients (47%) transplanted with active disease had stage III–IV disease and 15% and 61% had high LDH and ß2 microglobulin serum levels, respectively. Age-adjusted IPI was 2 or 3 in 51 patients (12%).


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Table 2. Patient characteristics at transplant
 
Table 3 shows the characteristics at diagnosis of 146 patients transplanted in 1st CR as compared with 94 transplanted in 2nd or 3rd CR. Table 4 shows patient characteristics at diagnosis according to the interval between last CR and transplantation (<6 months, n = 196; >6 months, n = 71).


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Table 3. Characteristics at diagnosis according to disease status at transplant
 

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Table 4. Characteristics at diagnosis according to interval between last complete remission (CR) and transplant
 
Transplant procedure
Source of autologous progenitor cells was bone marrow in 163 patients (36%), mobilised peripheral blood in 237 (52%) and both in 51 (11%). The product was purged in 10 patients. Overall, 398 patients were conditioned with chemotherapy: BEAM (carmustine, etoposide, cytarabine and melphalan; 178 patients, 39%), BEAC (carmustine, etoposide, cytarabine and cyclophosphamide; 151 patients, 33%), CBV (carmustine, etoposide and cyclophosphamide; 44 patients, 10%) and other (25 patients, 5%). The remaining 58 patients (12%) received cyclophosphamide plus total body irradiation (TBI). 305 (68%) received granulocyte colony-stimulating factor (G-CSF) (275) or granulocyte macrophage colony-stimulating factor (GM-CSF) (30) after the transplant whereas 141 patients (31%) did not receive cytokines after infusion.

Statistical analysis
In order to analyse which factors influence OS and disease-free survival (DFS), all clinical and biological characteristics at diagnosis and at transplantation were included in univariate analysis. Those factors with statistically significant influence on OS or DFS in univariate analysis were included in multivariate analysis. These variables are specified in Tables 1 and 2. ß2 Microglobulin levels at transplantation were not included in multivariate analysis due to the number of cases lacking this information. Overall survival analysis was performed both including and excluding response to transplantation. The year of the transplant was also included in the analysis for DFS and OS. The most significant cut-off in univariate analysis (1984–1990 and 1991–1999) was included in multivariate analysis.

Overall survival was calculated from the day of progenitor cells infusion to the date of death or last follow-up. Disease-free survival was calculated from the day of progenitor cells infusion until date of relapse or progression. Failure to reach CR or relapse/progression were considered events. Probabilities were estimated by the Kaplan–Meier method [23]. Differences in survival between groups according to the different covariates were analysed using the log-rank test [24]. A forward stepwise Cox proportional hazards regression model was used for multivariate analysis [25]. Proportionality of all variables included in Cox models have been confirmed by graphical assessment of proportional hazards. All P values reported are two-sided and statistical significance is defined as a value of P <0.05.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Response to HDT and survival
Response to transplantation was evaluated at 3 months. At that time, all patients transplanted in CR (141 in 1st CR and 94 in >=2nd CR) remained in CR. Concerning the 157 patients transplanted with sensitive disease (95 patients in 1st PR and 62 in 2nd PR), 66% reached CR, 12% remained in PR and the remaining 16% were considered non-responders (10%) or had progressive disease (6%). Concerning the 55 patients transplanted in progressive disease (primary and relapsed resistant disease), 25% achieved CR and 20% PR after the transplant, whereas 47% did not respond.

With a median follow-up of 31 months (range 0–169), 216 (48%) patients were alive without disease, 51 patients had relapsed (11%) and 185 (41%) had died, mainly due to disease progression (132; 29%). Overall survival and DFS at 5 years were 53% and 43%, respectively. The transplant-related mortality (TRM) was 11% (53 cases). Causes of death are listed in Table 5.


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Table 5. Causes of death
 
Analysis of prognostic factors
To assess which factors significantly affect OS and DFS, both univariate and multivariate Cox regression analysis were performed. On multivariate analysis three variables significantly influenced DFS (Table 6): number of protocols to reach 1st CR, disease status at transplantation and TBI in the conditioning regimen. Concerning OS (Tables 7 and 8), response to transplantation and type of conditioning regimen were the variables with significant influence on outcome in multivariate analysis. In order to analyse which variables prior to or at transplantation significantly affect outcome in LCL patients, and considering that response to transplantation depends on disease status at transplantation as shown before, a multivariate analysis was performed excluding response to transplantation. In this analysis the variables significantly affecting outcome were number of protocols to reach 1st CR, disease status at transplantation, IPI <60 at transplantation and conditioning regimen.


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Table 6. Univariate and multivariate analysis of prognostic factors for disease-free survival (DFS; n = 452)
 

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Table 7. Univariate and multivariate analysis of prognostic factors for overall survival (OS; n = 452)
 

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Table 8. Multivariate analysis for overall survival (OS)
 
Patients who needed more than one regimen to reach 1st CR had a significantly lower DFS and OS at 5 years as compared with those who reached 1st CR after one regimen (DFS of 31% versus 47%, P <0.0001, respectively, and OS of 38% versus 59%, P <0.0001, respectively; Figure 1). Concerning disease status at the time of transplantation, the 146 patients transplanted in 1st CR had a significantly better DFS (65 versus 37% at 5 years, P = 0.0001) and OS (74% versus 55% at 5 years, P = 0.01) as compared with the group of 94 patients transplanted in >=2nd CR (Figure 2), even though analysis of characteristics at diagnosis of patients undergoing HDT in 1st CR showed a higher percentage of patients with bulky disease as compared with >=2nd CR patients (59% versus 40%, P = 0.005) (Table 3). In addition, a higher percentage of patients transplanted in 1st CR needed more than one regimen to reach CR (23% versus 8%, P = 0.005).



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Figure 1. Survival according to number of protocols to reach 1st CR. (A) Disease-free survival; (B) overall survival.

 


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Figure 2. Survival according to status at transplant. (A) Disease-free survival; (B) overall survival.

 
Patients receiving conditioning regimen with cyclophosphamide plus TBI had a DFS and OS at 5 years of 29% and 29% versus 44% and 57% for patients receiving chemotherapy regimens, respectively (Figure 3). Variables which significantly influenced DFS and OS were similar among patients receiving TBI or polichemotherapy-based regimens except for a higher percentage of patients receiving TBI being transplanted before 1990 (30% versus 6%, P = 0.001); also, a higher percentage of patients in the TBI group had progressive disease as compared with those in the non-TBI group (26% versus 11%, P = 0.01).



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Figure 3. Projected overall survival according to conditioning regimen.

 
Response to transplant significantly influences OS: 64% of patients in CR 3 months after HDT were alive at 5 years versus 17% and 4% of PR and non-responder patients, respectively (P = 0.001). Finally, as shown in Table 7, age-adjusted IPI at transplantation also predicts survival after HDT, with 66%, 34%, 10% and 0% of patients with IPI 0, 1, 2 or 3 alive at 5 years, respectively.

It is also interesting to point out that interval from last CR to transplantation significantly influences DFS and OS in univariate analysis: patients undergoing HDT within an interval of 6 months between last CR to transplantation had a better OS (66% at 5 years) as compared with those transplanted after a longer interval (41% at 5 years, P <0.0002) (Tables 6 and 7). This result is especially significant if we consider that patients transplanted within a shorter interval had worse prognostic factors at diagnosis (Table 4): higher percentage of patients with an IPI of 2/3 (61% versus 44%, P = 0.04), a higher incidence of bulky disease (53% versus 34%, P = 0.01) and higher levels of LDH (64% versus 44%, P = 0.01) (Table 4).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Standard chemotherapy cures a significant proportion of DLCL patients. However, at least 50% of DLCL patients will finally die of their disease [12]. Although half of refractory/relapsing patients respond to salvage therapy, <10% will be finally cured by standard doses [2628]. In order to improve prognosis in this cohort of patients, HDT followed by stem cell support has been widely used and may result in longer-term DFS in more than half of the patients transplanted with sensitive disease [69].

In this study we report the results on 452 DLCL patients, included in the GEL-TAMO Data Base Registry, transplanted between 1984 and June 1999. Multivariate analysis has shown that status at transplant was one of the most important variables influencing both DFS and OS, with patients transplanted in 1st CR showing the best results after HDT. Concerning patients undergoing transplantation in 1st CR, the role of HDT as consolidation treatment remains unclear. Several recent randomised prospective trials have compared up-front HDT to conventional induction treatment in poor prognosis patients in 1st CR or PR [1221]. However, these studies differ both in their design and conclusions. One of the earliest published randomised trials [12] compared high-dose sequential therapy versus MACOP-B in 100 patients with bulky disease or advanced stage disease; patients in the transplant arm had a significantly superior EFS rate (76% versus 49%, P = 004). However, OS did not significantly differ between both groups (81% versus 55%, P = 0.09), probably due to the early toxicity and study cross-over design. In two other additional studies using standard induction chemotherapy [1315], although none of them show significant differences in terms of OS or DFS, in the GELA study [1314], a retrospective analysis showed that patients with an IPI of 2 or 3 receiving HDT had a better outcome as compared with those in the sequential arm, with a DFS of 55% versus 39% (P = 0.2) and OS of 64% versus 49% (P = 0.4) at 8 years, respectively. Also, in the study by Santini et al. [15], results in patients with unfavourable IPI scores suggest a benefit for the HDT arm. In contrast to these above-mentioned studies, in an EORTC trial [21] eight CHOP-like cycles were compared with six CHOP-like cycles plus BEAC: no differences were observed. However, it is important to point out that most of the patients in this study had a favourable IPI. Finally, five other studies [1620] show no advantage in the HDT arm. All of them contained a short (three cycle) standard induction therapy and early HDT.

In the current study, 146 patients underwent HDT in 1st CR and the 5-year DFS and OS values for this group were 65% and 74%, respectively. These patients did significantly better as compared with those transplanted in PR or even in >=2nd CR, since patients transplanted in >=2nd CR had a significantly higher relapse rate (19% versus 44%, P <0.0001). Interestingly, when we analysed the characteristics at diagnosis of patients undergoing HDT in 1st CR, they had a worse prognosis as compared with those transplanted in 2nd CR: 59% of the former patients had bulky disease as compared with 40% of patients transplanted in >=2nd CR (P = 0.005). Also a higher percentage of patients transplanted in 1st CR needed more than one regimen to reach CR as compared with the 2nd CR patient group (23% versus 8%, P = 0.005), and this was an independent prognostic factor in the multivariate analysis for DFS and OS (Tables 6 and 7).

Concerning patients with sensitive disease, we did not find significant differences in DFS and OS between patients transplanted in 2nd CR and those undergoing HDT with active sensitive disease (OS at 5 years 55% versus 47%, P = 0.5 and DFS at 5 years 36% versus 39%, P = 0.1). Our results are similar to those reported by Philip et al. [8], where EFS at 5 years was 46% for HDT versus 12% for the conventional treatment arm, and are also in agreement with those recently reported [29, 30]. In the study by Kewalramani et al. [29], in patients resistant to anthracycline-containing regimens, the 3-year EFS and OS were 44% and 52% for those patients responding to the salvage ICE regimen. Similar results have been communicated by Vose et al. [30]; in this multicentre study, patients who had never achieved CR but who are still chemosensitive had a progression-free survival and OS at 5 years of 31% and 37%, respectively.

Finally, with respect to primary or relapsing refractory patients, only eight of 55 (14%) in our series reached CR after the transplant and from them only 7% were long-term survivors. This and other series [7, 3133] confirm that HDT should probably not be offered to these patients and that they are possible candidates for newer strategies. It is important to note that, as shown in Tables 3 and 4, the longer the interval between diagnosis and transplant, or between last CR and transplant, the worst the disease status at transplant, which suggests that patients considered as candidates to receive an autologous transplantation should undergo the transplant early in the course of the disease.

We also found in multivariate analysis that those patients who reached 1st CR after one line of treatment did significantly better than those who needed more than one line of therapy in terms of DFS and OS (47% versus 31%, P <0.0001 and 59% versus 38%, P <0.0001 at 5 years, respectively). These data are in agreement with the work of Armitage et al. [34] in which patients with an early response (defined as a CR after three CAP-BOP courses) had a better prognosis and our data would suggest that the best induction scheme should be employed up-front in order to induce early CR in patients considered candidates to HDT.

The role of TBI in autologous transplantation has not been so clearly defined as compared with the allogeneic setting. A recent publication by the GEL-TAMO group on Hodgkin’s disease [35] has reported TBI as an independent prognostic factor adversely affecting survival in Hodgkin’s disease patients undergoing HDT. Our results in NHL patients would be in accordance to this study, since in our series of patients, those receiving TBI had a higher risk of death (RR = 2.15, 95% CI 1.5–3.1) as compared with those patients receiving chemotherapy-based conditioning regimens.

Another interesting feature of this study was that a shorter interval between last CR and transplant significantly influenced OS and DFS in univariate analysis, with patients who underwent HDT within 6 months of their last CR showing an OS at 5 years of 66% versus 41% for those patients transplanted later on. Interestingly, the former group of patients displayed worse prognostic factors at diagnosis: significantly higher incidence of bulky disease, higher levels of LDH and a higher incidence of IPI scores of 2 and 3 (Table 4).

The TRM of the present series (11%) compares favourably with other studies [611]. Five patients (0.9%) have died due to myelodisplastic syndrome. This rate is lower than the 12% and 8% recently published by Apostalidis et al. [36] and Chen et al. [37] in untransformed and transformed follicular lymphoma patients receiving autologous transplant, but similar to that reported in a study by Haioun et al. [14] and this could be related to the lower number of lines of chemotherapy administered before HDT in DLCL as compared with follicular lymphoma. Moreover, few patients in our series and none in the series of Haioun et al. [14] received TBI in the conditioning regimen, whereas in the previous studies [3637] all patients received TBI.

In conclusion, our results suggest that the best line of chemotherapy should be used up-front in patients considered as candidates for HDT in order to obtain an early CR. Transplantation should be performed early after 1st CR in high-risk patients in order to avoid resistance. Resistant patients are not good candidates for HDT and they should be offered newer strategies. Finally, polichemotherapy conditioning regimens, such as BEAM, offer better results as compared with TBI.


    Acknowledgements
 
We would like to thank Javier Martín Vallejo, Profesor de Estadística, University of Salamanca.


    Footnotes
 
+ Correspondence to: Dr Dolores Caballero, Hematology Service, University Hospital of Salamanca, Paseo de San Vicente s/n 37007 Salamanca, Spain. Tel: +34-923-291384; Fax: +34-923-294624; E-mail: cabarri{at}usal.es Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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