First Turkish allogeneic bone marrow transplantation for lymphomas was commenced in 1987, whereas autologous bone marrow transplantation in 1992 and PBSCT in 1993. The Turkish Bone Marrow Transplantation Registry (TBMTR) was founded in 1995 and nationwide data accumulation for hematopoietic stem cell transplantation (HSCT) has been done since then. A total of 15 centers participate actively in bone marrow and PBSC transplantation activities and report their results regularly to the registry.

This is the first published report for long-term results of HSCT activity and outcomes in Turkey. Here, we evaluate retrospectively the results of patients with Hodgkin's and non-Hodgkin's lymphoma who underwent autologous transplantation from 1992 until 2002 in Turkish bone marrow transplantation (BMT) centers.

Disease status of the patients before the transplantation were relapse and primary refractory disease for Hodgkin's lymphoma and sensitive relapse, resistant relapse, first complete or partial remission (CR1/PR1) and primary refractory disease for non-Hodgkin's lymphoma patients.

Data collection
Each transplantation center in Turkey has been requested to contribute data to the Registry and data of 15 transplantation centers registered in TBMTR were analyzed retrospectively beginning from 1992 to 2002. A standard Med-A form was completed at each center and sent to registry center for each transplantation. The presence or absence of relapse and the disease status of the patient and cause of death was requested to each center in annual basis.

The date of autologous HSCT was noted as day 0 and follow-up date was the date of the last medical examination.

Statistical analysis
Probabilities of 100-day mortality (death from any cause in the first 100 days after transplantation) and overall survival were calculated using SPSS 9.0 statistical software by the method of Kaplan-Meier (SPSS Inc, Chicago, IL, USA). Overall survival was measured from the date of transplantation (stem cell infusion) to the date of death from any cause or the last follow-up evaluation.

Hodgkin's lymphoma
Patient characteristics for the entire group are shown in table 1. One-hundred and eighty-five patients were Hodgkin's lymphoma with a male to female ratio of 125/60. The median age of the patients was 23 years (range: 15-64). One-hundred and fifty-nine patients out of 185 were relapse cases and 26 out of 185 were primary refractory disease at the time of transplantation. Histopathologic subclassification were mixed cellular (48%), nodular sclerosing (25%), lymphocyte-predominant (13%), lym-phocyte-depleted (7%) and pathology unknown (7%).

Table 1: Characteristics of patients with Hodgkin's lymphoma

Non-Hodgkin's lymphoma
Patients' characteristics are given in table 2. Two-hundred and fifty-two patients were non-Hodgkin's lymphoma. The median age of the patients was 36 years (range: 15-65) with 189 male and 63 female. The histopathologic subtype of the disease was diffuse large B cell (47%), precursor T lymphoblastic (18.8%), mantle cell (6.92%), peripheral T cell (6.92%), anaplastic large cell (5.42%), follicular (4.74%), immunoblastic (4.34%), Burkitt's (3.25%), nodal marginal zone B cell (1.62%), mycosis fungoides (1.08%).

Table 2: Characteristics of patients with non-Hodgkin's lymphoma

Hematopoietic stem cell sources and conditioning regimens
Bone marrow (3%), bone marrow with peripheral blood (<1%), peripheral blood with CD34+ selection (3%) and peripheral blood (94%) were used as sources of hematopoietic stem cells.

Non-TBI (total body irradiation) conditioning regimens were used in 88% of the transplantations [BEAM (BCNU, etoposide, cytarabine and melphalan) vs. CBV (cyclophosphamide, BCNU, etoposide)], whereas 12% of the patients underwent TBI containing conditioning regimens for lymphoma.

Outcome
100-day transplantation-related mortality rate was 11% in all Hodgkin's lymphomas including relapsed and primary refractory cases; whereas the rate was 15% in all non-Hodgkin's lymphomas (9% in CR1/PR1, 13% in sensitive relapse, 22% in primary refractory cases and 3% in resistant relapse) (Table 3).

Table 3: Transplant-related mortality (TRM) in patients with Hodgkin's and non-Hodgkin's lymphoma

The main cause of death in all patients was the relapse of the primary disease (86%) in addition to transplantation-related mortality (14%).

The overall survival rate was 50% in all patients with Hodgkin's lymphoma at 10-year follow-up (Figure 1), 50% in relapsed cases at 10th year (Figure 2) and 49% in primary refractory cases at 5^th year (Figure 3); whereas, in patients with non-Hodgkin's lymphoma the overall survival rate at 10th year was 45% in all cases (Figure 4), 65% at 10^th year for CR1/PR1 (first complete/partial remission) (Figure 5), 50% at 7^th year for sensitive relapse (Figure 6), 24% at 3rd year for primary refractory disease (Figure 7) and 0% at 2nd year for resistant relapse (Figure 8).

Fig 1: Survival of all patients with Hodgkin's lymphoma

Fig 2: Survival of patients with Hodgkin's lymphoma with relapse

Fig 3: Survival of patients with Hodgkin's lymphoma with primary refractory disease

Fig 4: Survival of all patients with non-Hodgkin's lymphoma

Fig 5: Survival of patients with non-Hodgkin's lymphoma with CR1/PR1

Fig 6: Survival of patients with non-Hodgkin's lymphoma with sensitive relapse

Fig 7: Survival of patients with non-Hodgkin's lymphoma with primary refractory disease

Fig 8: Survival of patients with non-Hodgkin's lymphoma with resistant relapse

It is well known that the majority of patients with advanced Hodgkin's lymphoma can be effectively treated with standard chemotherapy[1]. Unfortunately, patients with primary resistant or relapsed disease have a relatively low chance of cure.

There are no randomized trials comparing conventional salvage chemotherapy to autologous transplantation in patients with Hodgkin's disease who have not achieved a complete remission with initial therapy. There are only two relatively small randomized clinical trials comparing high-dose with standard-dose chemotherapy in high-risk Hodgkin's lymphoma showing a 4-year event-free survival rate of 50%[2-4]. Some reports have also suggested that patients with Hodgkin's lymphoma with primary refractory disease do less well than those patients who achieved an initial remission to front-line therapy[5].

In fact, autologous HSCT seems to be the best curative option for patients with relapsed and primary refractory Hodgkin's lymphoma[2,6,7]. Recently, encouraging reports on high-dose chemotherapy in primary refractory Hodgkin's disease have been published worldwide[5,8-11]. Reported 5-year overall survival probability is 35-60% in patients with primary resistant disease and 50-65% in patients who have relapsed after standard therapy[8-12]. Moskowitz et al.[13] found a marked survival advantage with HSCT for patients who have chemosensitive Hodgkin's disease; however overall survival was similar for patients with relapsed or primary refractory disease.

Our study findings indicate that autologous HSCT can lead to durable remissions in 50% of patients with primary refractory or relapsed Hodgkin's lymphoma patients which is consistent with other study results, as well as with those of ABMTR[8,14,15].

Anthracycline-based induction chemotherapy pro-duces complete remission rates of 50% to 70% and long-term disease-free survival in approximately 40% of patients with aggressive non-Hodgkin's lymphoma[16, The benefit of autologous HSCT in patients without complete remission by their initial induction chemotherapy is not well defined. GEL/TAMO trial[18] demonstrated a 5-year survival response of 43% in patients who failed to achieve complete remission with front-line conventional chemotherapy. Whereas, the Parma trial[19] is the first study which randomized patients with chemotherapy-sensitive relapsed disease to either standard salvage chemotherapy or autologous HSCT, and demonstrated improved progression-free survival and overall survival in the transplantation group. SWOG phase-II study[20] showed similarly that autologous bone marrow transplantation prolongs survival in relapsed non-Hodgkin's lymphomas. Mills et al.[21] reported a progression-free survival rate of 32% in patients with chemotherapy-sensitive relapsed disease. Many other studies containing small numbers of patients demonstrated progression-free survival rates of 30% to 40% [18,22,23]. Another study from ABMT showed a better outcome in chemotherapy-sensitive disease with a survival rate of 44% at 3-year[24]. Our survival outcome was 50% at 85 month follow-up for patients with sensitive relapse and is comparable to these studies.

Sensitivity to chemotherapy in relapsed non-Hodgkin's lymphoma is of prognostic significance. Relapse-free survival rate after autologous transplantation was 0-15% in the primary refractory group and 15-30% in the sensitive relapsed group[25]. Philip et al.[26] reported an event-free survival of 10-15%, which is similar to that observed with standard-dose salvage regimens in patients with refractory relapsed non-Hodgkin's lymphoma. Many subsequent studies of transplantation excluded such truly primary refractory patients from transplantation and better results were observed in chemosensitive patients than chemoresistant primary failures[23]. We haven't excluded patients with primary refractory disease from the study and we found a low rate of survival as 24% at 40-month follow-up consistently with these studies.

Despite controversy, some randomized controlled trials showed positive value for autologous HSCT as an initial treatment for high-intermediate and high-risk non-Hodgkin's lymphoma: the GELA[27] and Milan[28] studies, and the Italian study by Santini et al.[29] reported that high-dose therapy with transplantation improves relapse-free survival and overall survival. This was prospectively confirmed by the recent GOELAMS study[30]. On the other hand, three other studies from an Italian group[31], the German Lymphoma Group[32], and Martelli et al.'s study[33] found no significant difference with respect to relapse-free survival and overall survival. Our results also confirm that early transplantation in the first complete and partial remission may increase the overall survival rate (65%) in aggressive non-Hodgkin's lymphoma.

With better selection of patients, improved supportive care and the introduction of blood stem cells, the early TRM associated with autologous HSCT has decreased to less than 5%[34,35]. According to ABMTR data, TRM rate is around 5-8% in Hodgkin's lymphoma and around 10% in non-Hodgkin's lymphoma. In our study, TRM was 11% in Hodgkin's and 15% in all non-Hodgkin's lymphoma cases. These rates are consistent with the results of international registries.

In summary, autologous HSCT leads to durable remission in the majority of patients with Hodgkin's disease and non-Hodgkin's lymphoma. However, chemoresistant relapsed and primary refractory patients with non-Hodgkin's lymphoma have a poorer survival than chemosensitive patients. Our transplantation results on lymphomas are similar to other single or multicenter study results.

ACKNOWLEDGEMENT
We are grateful to Dr. Mustafa Turan from Gülhane Military Medical Academy, Department of Hydroclimatology for helping us in statistical analysis.

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