Departments of Blood and Marrow Transplantation and Lymphoma, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
Received 4 October 2002; revised 9 January 2003; accepted 21 January 2003
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Abstract |
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The aim of this study was to compare the outcomes of high-dose therapy (HDT) and allogeneic versus autologous hematopoietic stem cell transplantation (SCT) in patients with refractory or recurrent indolent non-Hodgkins lymphoma (NHL).
Patients and methods:
From January 1991 to March 2000, 112 patients underwent HDT followed by either autologous (68 patients) or allogeneic (44 patients) SCT for refractory or recurrent indolent NHL. Prior conventional chemotherapy had failed in all patients.
Results:
The two groups were similar with respect to age at transplantation, gender, histological subtypes, number of chemotherapy regimens received before transplantation and International Prognostic Index scores. The median time from diagnosis to transplantation was longer in the autologous than in the allogeneic SCT group (46 versus 27 months, P = 0.002). In the allogeneic SCT group the median follow-up time was 53 months (range 21113), and the overall survival (OS) and disease-free survival (DFS) rates were 49% and 45%, respectively. After a median follow-up time of 71 months (range 22109), in the autologous SCT group, the OS and DFS rates were 34% and 17%, respectively. Patients who underwent autologous SCT were more likely to have chemosensitive disease (P <0.001) and were more likely to be in complete remission at the time of transplantation (P = 0.001) than those who underwent allogeneic SCT. However, the probability of disease progression was significantly higher in the autologous SCT group than in the allogeneic SCT group (74% versus 19%, P = 0.003).
Conclusions:
Patients who undergo HDT with allogeneic SCT for refractory or recurrent indolent NHL have lower relapse rates but higher treatment-related mortality rates than patients who undergo autologous SCT. However, with the development of non-myeloablative preparative regimens, which can decrease treatment-related mortality, patients with recurrent indolent NHL should be considered for controlled trials of allogeneic transplantation if they have a human leukocyte antigen-identical donor.
Key words: allogeneic stem cell transplantation, autologous stem cell transplantation, indolent non-Hodgkins lymphoma
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Introduction |
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Patients and methods |
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Collection and processing of progenitor cells
Bone marrow (BM) was obtained by multiple aspirations from the right and left iliac crest under general anesthesia. A total of 10001500 ml of marrow were obtained for a target total nucleated cell dose of at least 3 x 108 cells/kg. For patients undergoing autologous SCT, peripheral blood stem cells (PBSCs) were obtained either during the steady state or during recovery from chemotherapy depending on the protocols for stem cell collection that were active at the time of study entry. The target dose was >4 x 106 CD34+ cells/kg. For allogeneic SCT, the stem cells were mobilized with recombinant human granulocyte colony-stimulating factor administered at a dose of 1012 µg/kg/day for 4 days. PBSCs were collected on the fourth day by large volume leukapheresis using continuous-flow cell separators until a target dose of 35 x 106 CD34+ cells/kg was obtained. All products were cryopreserved using standard techniques. In 56 of 68 patients undergoing autologous SCT, the mononuclear cell product was purged using anti-CD19 monoclonal antibodies as previously described [12]. All allogeneic transplant recipients received unmanipulated grafts.
Preparative regimens and transplantation
The preparative regimen consisted of etoposide, 1500 mg/m2 for 1 day; cyclophosphamide, 60 mg/kg for 2 days; mesna; and fractionated total-body irradiation (TBI) (10.2 or 12 Gy). Patients who were not eligible for TBI because of prior exposure to radiation received BEAM (carmustineetoposidecytarabinemelphalan) as the preparative conditioning regimen. Graft-versus-host disease (GVHD) prophylaxis consisted of a combination of ciclosporin or tacrolimus with mini-dose methotrexate and/or methylprednisolone (Table 1). M. D. Andersons supportive care guidelines were followed in regard to antibiotic prophylaxis, administration of growth factors, blood product support and treatment of neutropenic fever. Nine patients received interferon- maintenance after autologous SCT at a dose of 13 million units three times a week for 542 months.
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CR was defined as the disappearance of all clinical evidence of lymphoma for a minimum of 4 weeks with no persisting symptoms related to the disease. When feasible, biopsy of any residual mass was performed. For a patient to be categorized as a complete responder, any residual masses had to remain unchanged for 6 months. PR was defined as >50% decrease in the sum of the products of the two longest diameters of all measurable lesions for at least 4 weeks, and non-measurable lesions also had to decrease by at least 50%. Additionally, no lesion could increase in size and no new lesions could appear. Disease progression was defined as >25% increase in the sum of the products of the two longest diameters of any measurable lesion or the appearance of a new lesion. Patients who achieved at least a PR with salvage chemotherapy administered before transplantation were considered to have chemosensitive disease and patients who had less than a PR were classified as chemoresistant.
Statistical analysis
Primary end points for the study were overall survival (OS) (time from SCT until death or last follow-up), disease-free survival (DFS) (time from SCT until disease relapse, disease progression, death during remission or last follow-up), and rate of disease progression (time from SCT until disease progression or relapse). Cumulative OS, DFS and disease progression rates were estimated by the KaplanMeier method. The log-rank test was used to compare OS, DFS and the rate of disease progression between the autologous and allogeneic SCT groups. Differences in patient characteristics were evaluated by the Wilcoxon rank sum test for continuous variables and by the 2 test for categorical variables [14]. Statistical significance was defined at 0.05. Analysis was performed using the statistics software package STATA 7.0 [15].
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Results |
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Early deaths
Fifteen of the 44 patients in the allogeneic SCT group died within the first 100 days. Six patients died of acute GVHD, five of infection, three of disease progression and one of liver failure. In the autologous SCT group, four of the 68 patients died within the first 100 days, all from infectious causes. The overall 100-day mortality rate was 34% in the allogeneic SCT group and 6% in the autologous SCT group (P <0.001).
Acute and chronic GVHD
Acute GVHD developed in 24 of 44 patients (55%) who underwent allogeneic SCT. In 18 of 24 patients, it was grade IIIV. Thirteen of the 29 patients (45%) who survived beyond day 100 developed chronic GVHD. It was extensive in seven of 13 patients, and the rest had limited chronic GVHD.
Secondary myelodysplastic syndrome/acute myelogenous leukemia
Four of 68 patients (6%) in the autologous SCT group developed secondary myelodysplastic syndrome/acute myelogenous leukemia (sMDS/sAML); all four of them died. No cases of sMDS/sAML were identified in the allogeneic SCT group.
OS, DFS and disease progression
In the allogeneic SCT group the median follow-up time was 53 months (range 21113), and the OS and DFS rates were 49% [95% confidence interval (CI) 33% to 63%] and 45% (95% CI 30% to 59%), respectively. After treatment and a median follow-up time of 71 months (range 22109), in the autologous SCT group, the OS and DFS rates were 34% (95% CI 17% to 52%) and 17% (95% CI 8% to 30%), respectively (Figures 1 and 2).
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Discussion |
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Other investigators have reported similar results. In a study by Verdonck [16], 18 patients underwent autologous SCT and 15 underwent allogeneic SCT. With a median follow-up of 25 months (range 466) in the allogeneic SCT group, the 3-year probabilities of OS and event-free survival (EFS) were 70% (95% CI 38% to 87%) and 70% (95% CI 38% to 87%), respectively, and the relapse rate was 0%. In the autologous SCT group, only three patients were alive and disease free at the time of the report with a 3-year probability of OS and EFS of 33% (95% CI 13% to 54%) and 22% (95% CI 7% to 43%), respectively. The relapse rate in the autologous SCT group was 78% (95% CI 57% to 93%). The differences were significant for EFS and relapse rate. Attal et al. [17] also observed a very low relapse rate after allogeneic SCT. In a retrospective matched case-controlled analysis from the French registry, 72 patients who had undergone allogeneic SCT for follicular NHL were matched with 144 patients who had undergone autologous SCT. The patients were matched on the basis of age, disease status at the time of transplantation and conditioning regimen. The median follow-up time was 34 months. The authors observed a relapse rate of 12% at 60 months after transplantation, with a plateau at 15 months in the allogeneic SCT group in contrast to a 55% relapse rate at 60 months in the autologous SCT group, without any plateau (P <0.001). In that study, the 4-year EFS rate was comparable in the two groups, i.e. 53% versus 45% in the allogeneic and autologous SCT groups, respectively. As expected, the transplant-related mortality rate was higher in the allogeneic SCT group than the autologous SCT group (30% versus 4%, P <0.001)
The lower relapse rate after allogeneic SCT is in part attributable to the absence of lymphoma cells in the graft. However, the major impact is believed to be due to the GVL effect. Several investigators have demonstrated a GVL effect in indolent NHL: where patients who relapsed after allogeneic SCT achieved CR after immunosuppressive treatment was tapered, after development of GVHD, or after infusion of donor lymphocytes [18, 19]. However, in spite of these observations, allogeneic transplantation has been used rarely in patients with indolent NHL because of the high treatment-related mortality, which ranges from 20% to 40% in most case series [11, 16, 20].
Novel successful strategies have been effective in reducing the early mortality rate associated with allogeneic SCT. This has been possible with the introduction of non-myeloablative preparative regimens [21, 22]. Twenty patients with indolent NHL, with a median age at transplantation of 51 years, underwent allogeneic SCT using a non-myeloablative preparative regimen at M. D. Anderson. The actuarial probability of being alive and in remission at 2 years was 84% (95% CI 57% to 94%). No relapses were observed after a median follow-up time of 21 months. The 100-day mortality rate was reduced to 5%, and the incidence of acute GVHD (grade IIIV) was reduced to 20% [23].
Many patients are not able to benefit from an allogeneic SCT because of the lack of an HLA-identical donor; therefore, several authors have evaluated the role of autologous SCT for indolent NHL [79]. There have been wide variations in the reported OS rates, which range from 86% to 66% at 28 years, and DFS rates, which range from 53% to 42% at 28 years [7-9]. The differences in outcomes of autologous SCT are related to various factors including selection criteria, patient characteristics, source of stem cells, purging, preparative regimen used, timing of transplantation and post-transplantation maintenance therapy. Therefore, a clear benefit of autologous SCT is not well established.
There is also concern regarding the high incidence of sMDS/sAML in patients who are long-term survivors of autologous SCT [2426]. Four of 68 patients (6%) in our study died because of the development of sMDS/sAML. This may be attributed to the use of TBI and etoposide as the pretransplantation conditioning regimen in the majority of our autologous SCT patients [26]. In addition, Micallef et al. [25] suggested that in autologous SCT, the BM microenvironment after HDT, together with the stress of engraftment, results in the growth of stem cells that may have sustained chemotherapy-induced mutations before HDT. These changes are not always detectable before transplantation by standard cytogenetic analysis. They also suggested that the damaged stem cells may be at a higher risk for mutations because of the altered BM microenvironment after HDT.
Several strategies have been used to improve the outcome after autologous SCT. These include the incorporation of radioimmunoconjugates into the ablative therapy [27, 28] and using unconjugated monoclonal antibodies like rituximab for the treatment of minimal residual disease after transplantation [29] or for in vivo purging of the graft [30]. Longer follow-up is needed to evaluate the impact of these strategies on the natural history of indolent NHL.
In conclusion, allogeneic SCT for indolent lymphomas is associated with lower relapse rates than autologous SCT. With the decrease in transplant-related mortality demonstrated with non-myeloablative regimens, patients with recurrent indolent NHL should be enrolled in controlled trials for allogeneic SCT if they have an HLA-identical donor.
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Footnotes |
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References |
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