© Borgis - Postępy Nauk Medycznych 6/2011, s. 473-478
*Grzegorz Helbig1, Tomasz Kandzia2, Marcin Kubeczko2, Maria Liszka2, Klaudyna Machura2, Małgorzata Makowska2, Tomasz Oleksy2, Sławomira Kyrcz-Krzemień1
Autologiczne przeszczepienie komórek macierzystych (ASCT) jako konsolidacja remisji wydłuża przeżycie chorym z chłoniakiem z obwodowych limfocytów T (PTCL)
Autologous stem cell transplantation (ASCT) as a remission consolidation offers a durable survival benefit in patients with peripheral T-cell lymphomas (PTCL)
1Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice
Head of Department: Prof. Sławomira Kyrcz-Krzemień
2Students Research Group, Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice
Head of Department: Prof. Sławomira Kyrcz-Krzemień
Wstęp. Obwodowe chłoniaki z limfocytów T (PTCL) obejmują heterogenną grupę nowotworów złośliwych o agresywnym przebiegu i złym rokowaniu przy zastosowaniu konwencjonalnej chemioterapii.
Materiał i metodyka. Dwudziestu dziewięciu chorych w zaawansowanych stadiach PTCL zostało poddanych zabiegowi autologicznego przeszczepienia komórek macierzystych (ASCT). Pacjenci byli transplantowani po uzyskaniu pierwszej bądź kolejnej całkowitej remisji (CR) lub częściowej odpowiedzi (PR) uzyskanej po konwencjonalnej chemioterapii.
Wyniki. Analiza objęła 29 pacjentów (15 mężczyzn i 14 kobiet) w medianie wieku 45 lat (zakres 20-66) w momencie postawienia rozpoznania. W badanej grupie znalazło się 13 chorych z obwodowym chłoniakiem z limfocytów T nieokreślonym (PTCL-U) i 16 z anaplastycznym chłoniakiem z dużych limfocytów T (ALCL). U większości pacjentów obserwowano znaczny stopień zaawansowania klinicznego (III lub IV) oraz obecność objawów B. Międzynarodowy wskaźnik rokowniczy IPI ≥ 2 odnotowano u 10 pacjentów z PTCL-U i 6 z ALCL. W chemioterapii indukcyjnej zastosowano schemat CHOP (mediana liczby cykli 6, zakres 1-10). Mediana liczby cykli chemioterapii przed ASCT wynosiła 8 (zakres 3-20) dla PTCL-U i 7 (zakres 3-18) dla ALCL. Status choroby w momencie przeszczepienia był następujący: 8 CR i 5 PR w grupie PTCL-U oraz 8 CR i 8 PR u chorych z ALCL. W kondycjonowaniu przed ASCT zastosowano schemat CBV lub BEAM, odpowiednio u 15 i 14 pacjentów. Spośród 29 chorych poddanych transplantacji, 7 zmarło z powodu progresji choroby. W CR pozostaje 22 pacjentów. Prawdopodobieństwo 3-letniego całkowitego przeżycia (OS) oraz przeżycia wolnego od choroby (DFS) wynosi odpowiednio 79 i 70%.
Wnioski. Wyniki naszej analizy potwierdzają, że ASCT jako leczenie konsolidujące remisję u chorych z PTCL jest bezpieczną i skuteczną opcją terapeutyczną.
Introduction. Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of malignancies which are characterized by an aggressive disease course and a poor outcome after conventional chemotherapy.
Material and methods. We analyzed the results of ASCT in 29 patients with advanced stage PTCL. Patients were transplanted after achieving first complete or partial remission after conventional chemotherapy.
Results. Twenty nine patients (15 male and 14 female) at a median age at diagnosis of 45 years (range 20-66 years) were analyzed. The study cohort included 13 with PTCL unspecified (PTCL-U) and 16 patients with anaplastic large cell lymphoma (ALCL). Most patients had advanced disease stage at diagnosis (III and IV Ann-Arbor) and B symptoms. International prognostic index (IPI) ≥ 2 was demonstrated in 10 PTCL-U and 6 ALCL patients. Induction chemotherapy consisted of a median of six CHOP cycles (range 1-10). The median number of all cycles before ASCT was 8 (range 3-20) and 7 (range 3-18) for PTCL-U and ALCL, respectively. The disease status at transplant was as follows: complete remission (CR; n = 8) and partial remission (PR; n = 5) for PTCL-U and 8 CR and 8 PR for ALCL. Conditioning regimen before ASCT consisted of CBV and BEAM for 15 and 14 patients, respectively. Among 29 transplanted patients, 7 died due to disease progression. 22 patients remain in CR. The 3-year probability of the overall survival (OS) and progression-free survival (PFS) for whole group were 79 and 70%, respectively.
Conclusions. We have confirmed that ASCT as consolidation therapy for PTCL is a safe and efficient procedure.
The peripheral T cell lymphomas (PTCL) comprise a heterogeneous group of malignancies accounting for 10% of all lymphomas. The most common types of PTCL are PTCL-unspecified (PTCL-U) and anaplastic large cell lymphoma (ALCL). ALCL is additionally characterized by the presence or absence of the anaplastic lymphoma kinase (ALK) protein. The patients with ALK-positive ALCL have superior outcome when compared with ALK-negative ALCL and PTCL-U. The latter have aggressive clinical course, patients are usually diagnosed in later disease stage and present with B symptoms. The probability of 5-year disease-free survival (DFS) is estimated to be less than 30% with conventional chemotherapy (1, 2). Current standard of care for PTCL remains to be defined. CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen has been established as first-line therapeutic option. Its use resulted in high proportion of responses but relapses were frequently observed (3). High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been offered as consolidation for patients in first remission as well as for relapsed/refractory disease. The long-term results are encouraging for patients transplanted in complete remission with the 5-year overall survival (OS) as high as 68%. Therefore it might be appropriate to offer ASCT especially in this setting (4). Herein we report the long-term results of ASCT as a consolidation for PTCL patients transplanted in complete or partial response.
Patients and methods
Patients selection and characteristics
Twenty nine patients (15 male and 14 female) at median age of 45 years (range 20-66) were submitted to ASCT in our center between 2000-2010. The management of patients after diagnosis followed common standards, but due to the fact, that some patients were referred for transplantation from other centers, not all data were available for all patients. A histological diagnosis was established by the local pathologist and the following subtypes were present: PTCL-U (n = 13) and ALCL ALK negative or unknown (n = 16). The disease stage was evaluated according to the Ann Arbor staging system. The diagnostic work-up included physical examination, blood and serum analysis, chest X-ray, computed tomography of the neck, chest, abdomen and pelvis. Bone marrow biopsy was taken at diagnosis and then repeated at the time of transplant. Patients were eligible for ASCT if they fulfilled the following criteria: 1) first or subsequent complete or partial remission after conventional chemotherapy; 2) ECOG status 0 to 2; 3) age < 70 years and 4) adequate hepatic, renal and cardiac function. All patients signed informed consent approved by local ethical committee. The clinical characteristics of patients was presented in table 1.
Table 1. Patients characteristics.
|Parameter||PTCL-U (n = 13)||ALCL (n = 16)||P value|
|Age (range)||46 (24-61)||39 (20-66)||n.s.|
|Ann Arbor stage III-IV||11||10||n.s.|
|IPI ≥ 2||10||6||n.s.|
|WBC count (x 109/L; range)||5.9 (2.5-25.3)||5.9 (2.6-16.2)||n.s.|
|Hgb concentration (g/dL; range)||11 (7.3-13.9)||12.2 (8.2-14.7)||n.s.|
|PLT count (x 109/L; range)||179 (34-261)||267 (161-683)||n.s.|
|Enlarged mediastinal lymph nodes||6||7||n.s.|
|Enlarged abdominal lymph nodes||6||4||n.s|
|Median number of prior chemotherapy cycles (range)||8 (3-20)||7 (3-18)||n.s.|
|Median lines of chemotherapy (different regimens)|
Legend: IPI = international prognostic index; WBC = white blood cell; Hgb = hemoglobin; Plt = platelet; PTCL-U = peripheral T-cell lymphoma-unspecified; ALCL = anaplastic large T-cell lymphoma.
Induction chemotherapy was uniform and consisted of CHOP regimen in all studied patients. Eleven patients were given second-line regimens including different, usually not anthracycline-based chemotherapeutic schema. Mobilized peripheral blood was the source of stem cells for ASCT in all patients. The most frequently used regimens for mobilization was IVE (ifosfamide, etoposide, epirubicin) plus G-CSF 10 ug/kg starting from day 5 until the last day of apheresis. The number of 2 x 106 CD34-positive cells/kg was considered sufficient to ASCT, but in 2 patients the number of transplanted CD34-positive cells was below this threshold. The apheresis product was processed, frozen to -85 C, stored and re-infused after conditioning completed. The preparative regimens included CBV (cyclophosphamide, BCNU, etoposide) in 15 and BEAM (BCNU, cytarabine, etoposide, melphalan) in 14 patients.
The response to therapy was evaluated at 1, 3 and 6 months after ASCT and 6 months thereafter. CR was defined as a disappearance of all disease-related symptoms and measurable lesions for at least 4 weeks; PR was defined as a > 50% decrease in the sum of the products of the two largest diameters of all measurable lesions for at least 4 weeks. A progressive disease was defined by any increase > 25% in the sum of the diameter of any measurable lesions or the appearance of a new lesion.
The probability of overall survival (OS) and progression-free survival (PFS) were calculated according to Kaplan-Meier method. All calculations were made from the date of transplantation. Comparisons between the variables were carried out by log-rank test. All variables found to have P value < 0.1 in univariate analysis were considered to be candidates for the stepwise Cox regression model. Statistical significance was defined at a P value <0.05. Transplant-related mortality (TRM) was defined as death within 100 days of high-dose therapy not related to the disease, relapse and progression.
Cell dose and engraftment
The median number of transplanted nucleated cells was 3.31 x 108/kg (range 1.41-13.4) and the median number of CD34-positive cells was 5.7 x 106/kg (range 1.14-17.2). All patients engrafted. The median time to neutrophil recovery was 13 days (range 10-18) and platelet count > 50 x 109/L was achieved after median of 16 days (range 9-33). There was no statistically significant difference in terms of the number of transplanted NC, CD34-positive cells and time to neutrophil and platelet recovery between PTCL-U and ALCL patients. One patient died within 100 days after transplant.
Adverse events and supportive care
Seventeen patients experienced infections during the period of post transplant pancytopenia. Grade 3 or 4 mucositis occurred in 8 patients and it was the most frequent complication. One patient developed severe pneumonia, but recovered soon after neutrophil increase. There was no difference in terms of the frequency of infections between PTCL-U and ALCL.
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