¹German Cancer Research Center, Heidelberg, Germany

²Department of Internal Medicine V, University of Heidelberg, Germany

Correspondence to: Dr M T Voso, Ist Semeiotica Medica, Universita' Cattolica S Cuore, Largo A Gemelli, 1, 00168 Rome, Italy

This is a report on 111 patients with advanced stage follicular lymphoma who where autografted using PBSC. Seventy patients were enrolled in first remission, whereas 41 were treated in second or higher remission. High-dose therapy consisted of total body irradiation plus cyclophosphamide in 103 patients, while eight patients received BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan). Autografts contained 8.1 ± 0.6 ´ 10⁶ CD34⁺ cells/kg body weight. At a median follow-up of 44.2 months from PBSCT (range 4.9-77.4 months), 93 patients are alive, with a probability of overall and relapse-free survival (RFS) of 83% and 64%, respectively. A significantly higher probability of relapse was associated with male gender, involvement of more than eight lymph node areas, extra-nodal manifestations other than bone marrow and PBSCT performed in second or higher remission. In the latter group of patients, previous radiotherapy was associated with poor prognosis. The relevance of chemosensitivity as a prognostic factor was reflected by a better RFS in patients who had achieved complete remission at the time of PBSC mobilization. In a multivariate analysis, involvement of eight or more lymph nodes and high-dose therapy performed in second or higher remission were independent prognostic factors. Bone Marrow Transplantation (2000) 25, 957-964.

follicular lymphoma; peripheral blood stem cell transplantation

Follicular lymphoma (FL) accounts for approximately 15% to 30% of newly diagnosed lymphomas. Despite the initial indolent clinical course and the high response rates to conventional therapy, most patients will ultimately develop refractory disease or present with transformation into an aggressive large cell lymphoma.^1,2,3,4 In a group of 513 patients with FL treated at Stanford the failure-free survival at 10 years was 25% but no plateau in the survival curve was observed.¹ This indicates the need for better treatment modalities, particularly for patients with advanced stage disease.

The role of dose-intensive therapy with hematopoietic stem cell support in aggressive lymphomas has been shown. In a prospective randomized study in patients with high-grade non-Hodgkin's lymphoma (NHL), Philip et al⁵ have analyzed the long-term outcome of patients with a chemosensitive relapse following conventional chemotherapy. The response rate after high-dose therapy with autologous bone marrow transplantation (ABMT) was 84%, compared with 44% after conventional therapy alone. At 5 years, patients treated with high-dose chemotherapy and ABMT showed a significantly better event-free and overall survival (OS) in comparison with patients receiving conventional dose chemotherapy.⁵ The role of high-dose therapy with hematopoietic stem cell support for patients with low-grade NHL is however still controversial.^6,7,8,9,10

In this report we have analyzed the outcome of 111 patients with follicular lymphoma who were treated with high-dose therapy with PBSC in our institution between 1991 and 1998. Particular emphasis was put on the identification of prognostic factors which have impact on the long-term outcome.

Patients and methods

Patients and treatment

Patients were eligible for this study if they were age 60 or less and had an advanced-stage follicular lymphoma (centrocytic-centroblastic NHL according to the Kiel classification, or grade II follicular center lymphoma according to the REAL classification). Advanced stage was defined as stage III-IV or stage II with bulky disease at the time of first diagnosis, or as relapse following conventional therapy. Additional criteria were a Karnofsky score above 80% and normal heart, lung, kidney and liver function. Informed consent was obtained from each patient before therapy. The study was conducted according to the guidelines of the Joint Ethical Committee of the University of Heidelberg. The cut-off date of this report is 31 December 1998.

Between September 1991 and September 1998, 111 patients were included in this study. Fifty-eight patients were females and 53 were males, with a median age of 45 years (range 21-59) (Table 1). Out of 70 patients enrolled in first remission, two had stage II disease with abdominal bulk, while 14 and 54 patients had stage III and IV disease, respectively. Forty-one patients were enrolled in second or higher remission (range 2-5), following conventional therapy (Table 2).

All patients autografted in first remission received induction therapy, consisting of a median of four cycles (range 2-21 cycles) of anthracycline-containing regimens. One patient additionally received involved-field radiotherapy as part of the first-line therapy. Thirty-nine of 41 patients enrolled in second or higher remission received a median of seven cycles of conventional cytotoxic chemotherapy (range 0-20), including 14 patients, who also had radiotherapy. Two patients received radiotherapy alone before PBSC mobilization (Table 2).

PBSCs were collected during granulocyte colony-stimulating factor (G-CSF)-enhanced marrow recovery (Neupogen; Amgen, Thousands Oaks, CA, 300 g s.c./day) following chemotherapy. In one patient, PBSC were mobilized using G-CSF alone. Mobilization regimens used were HAM (cytosine-arabinoside, 2 g/m² every 12 h on days 1 and 2, and mitoxantrone, 10 mg/m², days 2 and 3) in 106 patients, DexaBEAM (dexamethasone, 24 mg/day, days 1-7, melphalan, 30 mg/m², day 2, carmustine, 60 mg/m², day 3, etoposide, 75 mg/m² and cytosine-arabinoside, 200 mg/m², days 4-7) (n = 2 patients), and two subsequent chemotherapy cycles in three patients (HAM/DexaBEAM and HAM/CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) (one patient)). CD34⁺ cells were selected in 15 patients using the Baxter Isolex 300 Magnetic Cell Separation Systems (Baxter Immunotherapy, Irvine, CA, USA).¹¹

The conditioning regimens consisted of total body irradiation (TBI) (14.4 Gy, hyperfractionated into eight fractions over 4 days) followed by cyclophosphamide (200 mg/kg) (n = 103 patients) or of BEAM (carmustine, 300 mg/m², etoposide, 1.2 g/m², cytosine-arabinoside, 800 mg/m², melphalan, 140 mg/m²) in eight patients who had previously received radiotherapy. No hematopoietic growth factors were administered following PBSCT.

Hematological reconstitution was defined as the median time to reach an absolute neutrophil count (ANC) of 0.5 ´ 10⁹/l and an unsubstituted platelet count of 20 ´ 10⁹/l.

Response evaluation

Follow-up restaging, including physical examination, blood counts and chemistry, bone marrow biopsy, chest X-ray and ultrasound of the abdomen, was performed at 3- to 6-month intervals following PBSCT. Computer-tomography of the chest and abdomen was performed in patients with previous bulky disease or with a suspicious chest X-ray or ultrasound of abdomen, respectively. Response was defined according to standard World Health Organization (WHO) criteria.

Overall survival was defined as the time between PBSCT and death or until last follow-up. Relapse-free survival (RFS) was defined as the time between PBSCT and recurrence of disease. Patients dying of treatment-related causes were excluded from the latter analysis. Patients with an adverse event following PBSCT were censored at the time of its occurrence.

Statistical analysis

Survival curves were estimated using the Kaplan-Meier product limit method. Univariate and multivariate analyses were performed to identify risk factors associated with overall and relapse-free survival. Differences between the survival curves were compared using the log-rank test and the Wilcoxon test. Multivariate analysis was performed using the Cox regression model with stepwise analysis (P values for entry = 0.15 and for removal = 0.05).

The following risk factors were first examined in a univariate analysis using the log rank test: age, sex, high-dose therapy in first remission vs second or higher remission, presence of bulky disease (tumor mass 5 cm in one diameter), involvement of eight or more lymph nodes, presence of extra-nodal involvement, BM involvement, splenomegaly, serum lactic dehydrogenase (LDH) levels, B symptoms at the time of start of conventional therapy. Disease status was analyzed at the time of PBSC mobilization and transplantation. The following lymph node areas were scored: right and left cervical, supraclavicular, axillar, iliacal and inguinal, mediastinal and retroperitoneal. A previous analysis performed by grouping patients according to the number of involved lymph nodes, indicated eight or more areas as cut-off. The stage of the disease was examined as a prognostic parameter in patients autografted in first remission, while previous radiotherapy and duration of first remission was taken into consideration in the group of patients autografted in second or higher remission. As a second step, variables which were significant in the univariate analysis were included in a multivariate analysis as stated above. Statistical computations were performed using the statistical software package SAS, version 6.11 (SAS Institute Inc, Heidelberg, Germany, 1995).

Results are expressed as mean ± standard error of the mean (s.e.m.) or as median and range.

Results

PBSC mobilization and transplantation

In 87 patients, PBSC were mobilized when best response was achieved following conventional anthracycline- containing chemotherapy. At that time, 20 patients were in complete remission (CR) and 67 in partial remission (PR). Twenty-four patients received mobilization therapy without previous induction. The mobilization therapy in 105 patients consisted of high-dose cytosine arabinoside and mitoxantrone, which resulted in a tumor response in 45 of the 91 patients (49.4%) with measurable disease (PR and relapse). As a consequence, 63 patients were in CR before the high-dose therapy was given, while 47 patients were in PR and one patient had no change (Table 2).

The patients received the PBSC-supported high-dose therapy at a median of 12.3 months following initial diagnosis (range 4.8-129 months). In 103 patients, high-dose therapy consisted of TBI plus cyclophosphamide, while BEAM was administered to eight patients. Following autografting with 8.1 ± 0.6 ´ 10⁶ CD34⁺ cells/kg body weight, 106 patients engrafted with a median time to a neutrophil count of 0.5 ´ 10⁹/l and a platelet count of 20 ´ 10⁹/l of 13 and 12 days (range 8-34 and 3-51), respectively. CD34-selected autografts were used in 15 patients.

Five patients (4.5%) died at a median of 17 days following PBSCT (range 13-188 days). One patient transplanted using 5.6 ´ 10⁶/kg BW selected CD34⁺ cells and another patient who received unseparated leukapheresis products, containing 4.9 ´ 10⁶ CD34⁺ cells/kg BW, had graft failure and died of sepsis and pneumonia, respectively. Two patients died of septicemia: Pseudomonas aeruginosa was isolated in one case, no bacteria could be isolated in the other case. One patient died of invasive pulmonary aspergillosis.

Patients remained in hospital for a median time of 18 days (range 9-124 days) following PBSCT and required a median of six platelet and four erythrocyte transfusions (range 2-37 and 0-48, respectively). They had a median of 4 days of fever over 38.5°C (range 0-43 days) and required intravenous antibiotic treatment for a median of 13 days (range 0-52 days). Thirty-seven patients received amphotericin-B for a median of 5.5 days (range 2-21 days).

Following PBSCT, three patients received adjuvant treatment with -interferon and four patients with irradiation to sites of bulky disease.

Therapeutic outcome

Excluding the five treatment-related deaths, 106 patients were evaluable for relapse-free survival. The 11 relapses in 65 patients autografted while in first remission were observed after a median follow-up of 13.8 months (range 0.3-42.5 months), while 17 of 41 patients autografted in second or higher remission, relapsed at a median follow-up of 12.7 months (range 4.6-44.8 months). Independent of the remission status, relapses occurred at sites of previous disease in 86% of patients, whereas exclusively new sites were noted in 14% of the patients (Table 3). Eight of 10 patients with BM relapse had a history of BM involvement during the course of the disease.

Outcome of relapse following PBSCT

Twenty-two of 28 patients received a therapy with palliative intention at the time of relapse. This included -interferon (11 patients), local radiotherapy (three patients), cytotoxic chemotherapy (one patient) and the administration of the humanized CD20-antibody (Rituximab, Roche, Basel, Switzerland) (one patient). In six patients a combination of chemotherapy and -interferon or CD20-antibody was given. As a result, 19 patients are alive at a median follow-up of 28.9 months (range 3-57.2 months) after the relapse was diagnosed. This group includes 11 patients autografted in second or higher remission.

Three patients transplanted in first remission and six patients transplanted in second or higher remission died of tumor progression following a median time of 7.3 months (range 0-16.5 months) after they had relapsed. Two patients without evidence of lymphoma died of complications related to a myelodysplastic syndrome at 32 and 20.6 months following PBSCT, while two patients died of multifocal encephalopathy and pneumonia at 22.2 and 10.4 months from PBSCT, respectively (Table 3).

The corresponding Kaplan-Meier estimate for relapse-free survival at a median of 44.2 months (range 4.9-77.4 months) following PBSCT was 64%, while the probability of overall survival was 83% (Figure 1).

Prognostic factors

Our analysis showed that male gender was associated with a higher risk of relapse (RFS: 79% vs 45%, P = 0.048) (Figure 2). Similarly, the probability of relapse was higher for patients with extensive disease, reflected by eight or more involved lymph node areas and extra-nodal involvement or leukemic presentation (RFS: 40% vs 78%, P = 0.001, and 59% vs 67%, P = 0.045, respectively) (Table 4, Figure 3). Bulky disease with a lymphoma mass greater than 5 cm in one diameter was present in 30 patients, with abdominal localization in 28 of them. Nineteen of these patients presented with a retroperitoneal bulk, which was larger than 10 cm. Nonetheless, independent of the size, the presence of bulky disease was not a prognostic factor. The probability of relapse-free survival was also not related to age, initial stage of the disease, presence of BM involvement and serum LDH levels (Table 4).

The relevance of chemosensitivity was reflected by a trend towards better prognosis for patients who had achieved CR before PBSC mobilization (57% vs 83%, P = 0.054) (Figure 4a). On the other hand, the probability of RFS was not related to the number of previous chemotherapy cycles or regimens administered. Confirming our previous data on a smaller number of patients,⁷ a significant difference in the probability of RFS was noted between patients transplanted in first remission and patients autografted in second or higher remission (78% vs 43%, P = 0.003) (Figure 4b). For the latter group of patients, previous irradiation was associated with a significantly worse prognosis (RFS: 21% vs 56%, P = 0.03) (Figure 5).

None of the 14 evaluable patients autografted with CD34-selected PBSC relapsed at a median follow-up of 12.9 months (range 4.9-24.3 months).

According to the multivariate analysis, the involvement of eight or more lymph node areas and high-dose therapy performed in second or higher remission were independent prognostic factors for disease recurrence (²-test: P = 0.001 and 0.009, respectively).

On the other hand, the presence of extra-nodal involvement, other than bone marrow, was the only variable that significantly adversely affected overall survival (72% vs 90%, P = 0.01) in the univariate analysis (Table 4).

Late effects of PBSCT

At a median of 11.9 months (range 8.7-20.9 months) following PBSCT, 10 patients had leukocyte counts below 4 ´ 10⁹/l, platelet counts below 150 ´ 10⁹/l and hemoglobin below 14 g/dl. Of the five patients with platelet counts below 100 ´ 10⁹/l over a median time of 11.7 months (range 8.9-17.4 months), one patient required platelet transfusions. Four patients had a hemoglobin below 10 g/dl, with two requiring erythrocyte transfusions. Five patients developed a secondary malignancy (two Hodgkin's disease, two myelodysplastic syndromes, and one gastric cancer) at a median of 32.4 months following PBSCT (range 8.7-50.7 months) (Table 3).

Discussion

In the present study, we report on the outcome of a group of 111 patients with advanced-stage follicular NHL, treated in our center between 1991 and 1998. The results obtained with our PBSC-supported high-dose therapy are in line with the results reported by Freedmann et al.⁹ At a median follow-up of 45 months, a RFS of 63% was observed in 77 patients with previously untreated stage III-IV FL.⁹ The patients were in CR following CHOP chemotherapy, and received bone marrow purged with anti-B cell monoclonal antibodies and complement, following a TBI-containing conditioning regimen. The 44% 4-year estimated probability of failure-free survival reported by Bierman et al¹² in 100 patients with FL, probably results from the inclusion of patients with refractory or recurrent follicular lymphoma. In their study, the only prognostic factor for overall and failure-free survival was the number of chemotherapy regimens given before autografting.

Although with a relatively short follow-up of approximately 4 years, the 64% probability of relapse-free survival of our patients is better than that reported in studies using conventional cytotoxic chemotherapy.^1,4,13,14 In a recent report on a group of 165 patients with previously untreated stage III-IV FL, an EFS of 35% at 4 years was observed.⁴ The patients were randomized to receive cyclophosphamide, vincristine, prednisone or mitoxantrone and prednimustine, followed by a second randomization for maintainance therapy with or without interferon.

By interpreting the data, one has to bear in mind that any transplantation study is hampered by a selection bias, as for instance the patients' median age is substantially lower than that of patients undergoing conventional therapy. The influence of the patients' age on treatment outcome was particularly demonstrated by Dana et al¹⁴ in a group of 415 patients treated with doxorubicin-based chemotherapy or chemo-immunotherapy: half of the patients aged less than 40, and 26% of those aged more than 60 were alive at a median follow-up of 10 years.

The International Prognostic Index, developed for patients with high-grade NHL, has also been applied to patients with follicular lymphoma,^15,16 but was not applicable to our analysis, since only young patients, with advanced-stage disease and a good performance status were included in our study. As proposed by Romaguera et al,¹³ patients' characteristics, like male gender and high tumor burden, indicate a group of patients at high-risk for relapse. This also relates to patients with relapse or progressive disease. Accordingly, in our patients the extent of the disease expressed as number of involved lymph node areas and extra-nodal involvement were negative prognostic factors. As reported by other groups,⁹ the relapse was predominantly localized at sites of previous disease, while 80% of patients with BM relapse had former marrow infiltration. These data suggest that the origin of relapse is residual tumor cells in vivo, resistant to the high-dose treatment.

In line with these results, we found that t(14;18) PCR-positivity in blood or bone marrow samples following PBSCT, was associated with an 4.5 estimated hazard ratio for relapse in comparison with a PCR-negative finding while continued PCR-negativity was associated with prolonged freedom from recurrence.¹⁷

The significance of contaminating PCR-positive cells in the autografts of patients with low-grade NHL is not clear.^4,7,17,18,19 Peripheral blood stem cells may contain fewer tumor cells than bone marrow^7,20,21 and patients autografted with a PCR-negative BM were reported to have significantly longer time of freedom from recurrence than those whose BM was PCR-positive (88% vs 51%).⁹ This could be simply an indicator for a lower tumor burden in vivo.

The toxicity of our treatment was moderate, with a rate of 4.5% treatment-related deaths. Secondary malignancies were rarely observed (4.5%) and involved the lympho- hematopoietic system in four patients, while one patient developed gastric cancer. These data are compatible with previous reports.^6,8,9,22 There was also a transient period of mild pancytopenia in 9% of patients, with two patients requiring blood transfusions. The delay of hematopoietic recovery observed in these patients might reflect the impairment of the hematopoietic microenvironment or insufficient homing following PBSCT.^23,24

In our patients, the 78% probability of relapse-free survival for patients autografted in first remission is encouraging. To improve these results we are evaluating the incorporation of the humanized CD20-antibody in the PBSC mobilization and conditioning regimens. In addition, ex vivo activated T cells loaded with a CD3xCD19 bi-specific antibody or B cell-specific antibodies conjugated with ²¹³Bismuth might be used as adjuvant treatment following high-dose therapy.

Acknowledgements

We wish to thank all the colleagues who during these years referred patients to our centre, the staff of the Transplantation Unit and of the Department of Radiology for the outstanding care of patients. The excellent technical assistance of Renate Alexi, Kirsten Flentje, Monika Hess, Evi Holdermann, Margit Pförsich, Petra Schmidt, Lena Volk and Mirjam Weis and the continuous secretarial help of Ursula Scheidler are also acknowledged.

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20 Vescio RA, Han EJ, Schiller GJ et al. Quantitative comparison of multiple myeloma tumor contamination in bone marrow harvest and leukapheresis autografts. Bone Marrow Transplant 1996; 18: 103-110, MEDLINE

21 Leonard BM, Hetu F, Busque L et al. Lymphoma cell burden in progenitor cell grafts measured by competitive polymerase chain reaction: less than one log difference between bone marrow and peripheral blood sources. Blood 1998; 91: 331-339, MEDLINE

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24 Voso MT, Murea S, Goldschmidt H et al. High dose therapy with peripheral blood stem cell transplantation results in a significant reduction of the haematopoietic progenitor cell compartment. Br J Haematol 1996; 94: 759-766, MEDLINE

Figure 1 Overall (OS) and relapse-free survival (RFS) in 111 patients with advanced stage follicular lymphoma following high-dose therapy and PBSCT. Patients dying of treatment-related causes were excluded from the RFS analysis. Patients who had an adverse event were censored at the time of occurrence of the latter.

Figure 2 Male patients had a higher probability of relapse following PBSCT than females.

Figure 3 Extension of disease and relapse-free survival. (a) Number of lymph-node areas involved and (b) extra-nodel involvement and leukemic presentation.

Figure 4 (a) Patients achieving complete remission (CR) at PBSC mobilization (MOB); and (b) those autografted in first remission had a significantly better relapse-free survival than those with measurable disease and enrolled in second or higher remission, respectively (PR = partial remission; R = relapse).

Figure 5 Previous radiotherapy was associated with a significantly worse probability of relapse-free survival in patients autografted in second or higher remission.

Table 1  Patients' characteristics

Table 2  Disease history

Table 3  Clinical outcome

Table 4  Prognostic factors