Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin’s lymphoma

C. Hosing, R. M. Saliba, P. McLaughlin, B. Andersson, M. A. Rodriguez, L. Fayad, F. Cabanillas, R. E. Champlin and I. F. Khouri+

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


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

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-Hodgkin’s 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 21–113), 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 22–109), 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-Hodgkin’s lymphoma


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Recurrent indolent non-Hodgkin’s lymphomas (NHLs) are generally considered incurable with conventional chemotherapy. Patients with advanced or refractory disease usually have a poor outcome with salvage therapy and ultimately die of their disease [1, 2]. Autologous stem cell transplantation (SCT) has frequently been used in these patients because these lymphomas are generally very sensitive to chemotherapy and radiation therapy, and because the mortality rate associated with autologous SCT has declined steadily over the years to <5% in most case series [3, 4]. The transplantation procedure has been performed for consolidation of first complete remission (CR) or partial remission (PR) or after relapse [4–10]. However, in all studies of autologous SCT for indolent NHL, a persistent tendency for relapse has been observed, and no convincing improvement in survival has been demonstrated. An earlier report from our institution was the first to demonstrate a trend towards a lower relapse rate for patients with indolent NHL who had received an allogeneic SCT [11]. Here we report the outcome of 112 patients with refractory or recurrent indolent NHL who underwent high-dose therapy (HDT) and autologous or allogeneic SCT at the University of Texas M. D. Anderson Cancer Center.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
We identified all patients with histologically proven indolent NHL who underwent HDT followed by either autologous or allogeneic SCT at our institution between January 1991 and March 2000. Data were collected from an institutional database of blood and marrow transplant recipients and from a review of patient records. All patients had recurrent follicular or small lymphocytic lymphoma after a prior response to conventional treatment. All patients had received salvage chemotherapy before transplantation. Before 1995, patients were considered for autologous SCT if they had chemosensitive disease and <10% marrow involvement with lymphoma at the time of harvest. Allogeneic SCT was reserved for patients with refractory disease and extensive marrow involvement (>=10%) who were £60 years of age. Since 1995, after the observation of lower relapse rates in patients receiving allogeneic SCT [11], all patients £60 years of age with an human leukocyte antigen (HLA)-identical or one-antigen-mismatched related donor were offered allogeneic transplantation upon failure of conventional chemotherapy. Patients who lacked an HLA-identical sibling donor and were also not eligible for autologous SCT underwent a matched unrelated donor transplant. Patients were required to have a good Zubrod performance status score (£2) and normal renal (serum creatinine <=2 mg/dl), hepatic (total serum bilirubin <=1.5 mg/dl), cardiac (left ventricular ejection fraction <50%) and pulmonary (diffusing capacity for carbon monoxide <50 mmHg) function. Patients with uncontrolled medical illness or active infection at the time of planned transplantation were not eligible to receive SCT. Written informed consent was obtained from all the patients and donors, and the treatment protocols were approved by the M. D. Anderson Cancer Center Institutional Review Board.

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 1000–1500 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 10–12 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 3–5 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 (carmustine–etoposide–cytarabine–melphalan) 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. Anderson’s 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-{alpha} maintenance after autologous SCT at a dose of 1–3 million units three times a week for 5–42 months.


View this table:
[in this window]
[in a new window]
 
Table 1.  Stem cell transplant (SCT) characteristics
 
Patient evaluation before transplantation consisted of physical examination, complete blood count, serum chemistry panel, chest radiography, computed tomography of the chest, abdomen and pelvis, gallium scan, and bilateral BM aspiration and biopsy. The studies were repeated at 1, 3 and 6 months after transplantation and every 6 months thereafter. Patients undergoing allogeneic transplantation also had chimerism studies performed 1 month after transplantation and as clinically indicated thereafter. GVHD was graded according to the Consensus Conference criteria [13].

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 Kaplan–Meier 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 {chi}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].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between January 1991 and March 2000, a total of 112 patients underwent HDT and SCT for refractory or recurrent indolent NHL at our institution. Sixty-eight patients received autologous grafts and 44 received allogeneic grafts. Patient characteristics are summarized in Table 2. At the time of transplantation, 26% of patients in the autologous SCT group were in CR, compared with only 2% in the allogeneic SCT group (P = 0.001). Thirty-five percent of patients in the autologous SCT group had received fludarabine for treatment of their lymphoma before transplantation, where as in the allogeneic SCT group 57% of patients had received fludarabine. Very few patients received rituximab before transplantation (allogeneic SCT, four patients; autologous SCT, one patient). In spite of this, the percentage of patients who had chemoresistant disease before transplantation was higher in the allogeneic SCT group than in the autologous SCT group (43% versus 9%, P <0.001). The median time from diagnosis to transplantation was 27 months (range 4–273) in the allogeneic SCT group versus 46 months (range 11–191) in the autologous SCT group (P = 0.002). This time difference can be attributed to the fact that patients in the autologous SCT group were more likely to have indolent disease and were more likely to have chemosensitive disease, whereas patients in the allogeneic SCT group were chemoresistant.


View this table:
[in this window]
[in a new window]
 
Table 2.  Stem cell transplantation (SCT) patient characteristics: data are numbers of patients unless otherwise indicated
 
Transplant characteristics
Transplant characteristics are summarized in Table 1. In the autologous SCT group, 85% of patients received stem cells from BM, whereas in the allogeneic SCT group, 41% of patients received stem cells from BM and 59% received PBSCs (P <0.001).

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 II–IV. 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 21–113), 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 22–109), 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).



View larger version (13K):
[in this window]
[in a new window]
 
Figure 1. Kaplan–Meier estimates of overall survival after high-dose therapy followed by autologous or allogeneic stem cell transplantation for refractory or recurrent indolent non-Hodgkin’s lymphoma.

 


View larger version (14K):
[in this window]
[in a new window]
 
Figure 2. Kaplan–Meier estimates of disease-free survival after high-dose therapy followed by autologous or allogeneic stem cell transplantation for refractory or recurrent indolent non-Hodgkin’s lymphoma.

 
Outcomes were initially more favorable for the autologous SCT group (significant only for day 100 mortality); however, this pattern changed over time. A plateau was seen among the allogeneic SCT group at 44 months after transplantation for OS and at 24 months for DFS, whereas there was a continuous pattern of treatment failure in the autologous SCT group. The improved OS among the allogeneic SCT group was not statistically significant (P >0.05) but the improved DFS was significant (P = 0.01). A similar pattern of DFS was observed when 19 patients with chemoresistant disease who underwent allogeneic SCT were compared with 26 patients with chemosensitive disease who underwent autologous SCT (P = 0.04) (Figure 3). The rate of disease progression was significantly higher in the autologous SCT group (74%; 95% CI 59% to 88%) than in the allogeneic SCT group (19%; 95% CI 9% to 38%) with P = 0.003 (Figure 4).



View larger version (15K):
[in this window]
[in a new window]
 
Figure 3. Kaplan–Meier estimates of disease-free survival in patients with chemoresistant disease who underwent allogeneic stem cell transplantation and those with chemosensitive disease who underwent autologous stem cell transplantation.

 


View larger version (13K):
[in this window]
[in a new window]
 
Figure 4. Kaplan–Meier estimates of disease progression after high-dose therapy followed by autologous or allogeneic stem cell transplantation for refractory or recurrent indolent non-Hodgkin’s lymphoma.

 
Evaluation of confounding factors such as disease status at the time of transplantation, chemosensitivity and source of stem cells (BM versus PBSCs) using multivariate analysis was not possible because of the skewed distribution of these factors among the two treatment groups.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the present study, we compared the outcomes of HDT followed by autologous versus allogeneic SCT in patients with refractory or recurrent indolent NHL. We found a higher relapse rate in patients who underwent autologous SCT than in those who underwent allogeneic SCT. No relapses were observed beyond day 430 after transplantation in the allogeneic SCT group, whereas in the autologous SCT group relapses were still observed as late as 8 years after transplantation. This is despite the fact that more patients in the autologous SCT group had chemosensitive disease and were in CR at the time of transplantation than in the allogeneic SCT group. A similar trend was noted when patients with chemosensitive disease who underwent autologous SCT were compared with patients with chemoresistant disease who underwent allogeneic SCT, although the number of patients in each group was small. This observation supports the presence of a graft-versus-lymphoma (GVL) effect seen with allogeneic SCT. The lower relapse rate in the allogeneic group did not translate into an improved OS rate because of a higher early mortality rate. However, it appears that at 5 years the OS curves of the autologous and allogeneic SCT groups cross and that with longer follow-up an improved survival rate for patients in the allogeneic SCT group may be more evident.

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 4–66) 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 II–IV) 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 [7–9]. There have been wide variations in the reported OS rates, which range from 86% to 66% at 2–8 years, and DFS rates, which range from 53% to 42% at 2–8 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 [24–26]. 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.


    Footnotes
 
+ Correspondence to: Dr I. F. Khouri, Department of Blood and Marrow Transplantation, Box 423, Houston, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-745-2803; Fax: +1-713-794-4902; E-mail: ikhouri{at}mdanderson.org Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Horning SJ. Treatment approaches to the low-grade lymphomas. Blood 1994; 83: 881–884.[Free Full Text]

2. Romaguera JE, McLaughlin P, North L et al. Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: a risk model. J Clin Oncol 1991; 9: 762–769.[Abstract]

3. Rohatiner AZS, Johnson PWM, Price CGA et al. Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 1994; 12: 1177–1184.[Abstract]

4. Schouten HC, Raemaekers JJ, Kluin-Nelemans HC et al. High-dose therapy followed by bone marrow transplantation for relapsed follicular non-Hodgkin’s lymphoma: Dutch HOVON Group. Ann Hematol 1996; 73: 273–277.[CrossRef][ISI][Medline]

5. Bierman PJ, Vose JM, Anderson JR et al. High dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin’s lymphoma. J Clin Oncol 1997; 15: 445–450.[Abstract]

6. Freedman AS, Neuberg D, Mauch P et al. Long term follow up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 1999; 94: 3325–3333.[Abstract/Free Full Text]

7. Cao TM, Horning SJ, Negrin RS et al. High-dose therapy and autologous hematopoietic-stem cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience. Biol Blood Marrow Transplant 2001; 7: 294–301.[ISI][Medline]

8. Horning SJ, Negrin RS, Hoppe RT et al. High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial. Blood 2001; 97: 404–409.[Abstract/Free Full Text]

9. Freedman A, Gribben J, Neuberg D et al. High dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 1996; 88: 2780–2786.[Abstract/Free Full Text]

10. Apostolidis J, Gupta RK, Grenzelias D et al. High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow up. J Clin Oncol 2000; 18: 527–536.[Abstract/Free Full Text]

11. van Besien KW, Khouri IF, Giralt S et al. Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: the case for aggressive management. J Clin Oncol 1995; 13: 1096–1102.[Abstract]

12. Reading CL, Thomas MW, Hickey CM et al. Magnetic affinity colloid (MAC) cell separation of leukemia cells from autologous bone marrow aspirates. Leuk Res 1987; 11: 1067–1077.[CrossRef][ISI][Medline]

13. Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.[ISI][Medline]

14. Wilcoxon F. Individual comparisons by ranking methods. Biometrics 1945; 1: 80–83.

15. StataCorp. Stata Statistical Software: release 7.0. College Station, TX: Stata Corporation 2001

16. Verdonck L. Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin’s lymphoma: updated results of the Utrecht experience. Leuk Lymphoma 1999; 34: 129–136.[ISI][Medline]

17. Attal M, Socié G, Molina L et al. Allogeneic bone marrow transplantation for refractory and recurrent follicular lymphoma: a case matched analysis with autologous transplantation from the French bone marrow transplant group registry data. Blood 1997; 90 (Suppl 1): 255a.

18. Jones RJ, Ambinder RF, Piantadosi S et al. Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 1991; 77: 649–653.[Abstract]

19. van Besien KW, de Lima M, Giralt S et al. Management of lymphoma recurrence after allogeneic transplantation: the relevance of a graft versus lymphoma effect. Bone Marrow Transplant 1997; 19: 977–982.[CrossRef][ISI][Medline]

20. Stein RS, Greer JP, Goodman S et al. High-dose therapy with autologous or allogeneic transplantation as salvage therapy for small-cleaved cell lymphoma of follicular center cell origin. Bone Marrow Transplant 1999; 23: 227–233.[CrossRef][ISI][Medline]

21. Khouri I, Keating M, Körbling M et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824.[Abstract]

22. Khouri I, Saliba R, Giralt S et al. Allogeneic hematopoietic transplantation for indolent lymphomas: improved outcome with non-myeloablative versus high dose chemotherapy (HDCT) regimens. Blood 2000; 96: 853a.

23. Khouri IF, Saliba RM, Giralt S et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98: 3595–3599.[Abstract/Free Full Text]

24. Pedersen-Bjergaard J, Pedersen M, Myhre J et al. High-risk of therapy-related leukemia after BEAM chemotherapy and autologous stem-cell transplantation for previously treated lymphomas is mainly related to primary chemotherapy and not to the BEAM transplantation procedure. Leukemia 1997; 11: 1654–1660.[CrossRef][ISI][Medline]

25. Micallef INM, Lillington DM, Apostolidis J et al. Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 2000; 18: 947–955.[Abstract/Free Full Text]

26. Hosing C, Munsell M, Yazji S et al. Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. Ann Oncol 2002; 13: 450–459.[Abstract/Free Full Text]

27. Press O, Eary J, Applebaum F et al. Phase II trial of 131-B1 (anti CD20) antibody therapy with autologous stem cell transplantation for relapsed B-cell lymphomas. Lancet 1995; 346: 336–340.[ISI][Medline]

28. Liu S, Eary J, Petersdorf S et al. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol 1998; 16: 3270–3278.[Abstract]

29. Buckstein R, Imrie K, Spaner D et al. High frequency of molecular remissions associated with rituxan or interferon immunotherapy following ASCT for follicular NHL. Blood 2000; 96: 3418a.

30. Magni M, DiNicola M, Devizzi L et al. Successful in vivo purging of CD 34 containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000; 96: 864–869.[Abstract/Free Full Text]