Autologous hematopoietic transplantation for low-grade lymphomas

Cytotherapy (2002) Vol. 4, No. 3, 205–215

Martin Dunitz

Taylor&Francis healthsciences

Autologous hematopoietic transplantation for low-grade lymphomas JG Gribben Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Background

Autologous stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed chemo-sensitive intermediate grade

than bone marrow as a source of stem cells. The role of purging of residual tumor cells remains controversial and no randomized trial has been published to date that could evaluate the clinical utility of

lymphoma, but its role in the treatment of low-grade lymphomas and in selected patients in first remission remains controversial.

cell manipulation to attempt to remove contaminating lymphoma cells. Secondary leukemia is emerging as a major source of long-term morbidity and mortality after autologous stem cell

Methods

transplantation.

A large number of clinical trials have evaluated the role autologous SCT in both low grade and intermediate grade non-Hodgkin’s lymphomas (NHL). These studies have attempted to evaluate the role of high dose therapy with stem cell support in comparison to more conventional chemotherapy approaches. Studies have also focused on methods to assess whether contaminating tumor cells are contained with the stem cell collection and whether this has impact on outcome. With an increased number of patients now long term survivors, additional studies are focusing on long term complications and in particular the emergence of secondary malignancies.

Conclusion

Autologous SCT is associated with improved outcome in patients with relapsed intermediate grade lymphoma and most likely prolongs disease free survival in patients with low grade NHL. Morbidity and mortality of the procedure is low and major efforts are being made to attempt to decrease the major causes of failure, which remain disease relapse and occurrence of secondary malignancies.

Keywords Results

Virtually all patients now receive peripheral blood stem cells rather

Role of SCT in low-grade lymphoid malignancies Although high-dose therapy (HDT) with stem-cell support has become the treatment of choice for patients with relapsed intermediate-grade lymphoma [1], the role of stem- cell therapy (SCT) in the management of patients with low-grade NHL remains more controversial. As shown in Table 1, there are many reasons why SCT has been used less frequently in patients with low-grade lymphoma. There has been reluctance to perform potentially lethal treatment procedures in diseases with relatively long natural histories, which tend to occur in more elderly patients. The very high

Low-grade non-Hodgkin’s lymphoma, CLL, mantle-cell lymphoma, stem-cell transplantation.

incidence of BM infiltration in these diseases has made it difficult to use autologous stem-cells for rescue after HDT. Lastly, although the indolent lymphomas are characterized by initial chemotherapy responsiveness, by the time SCT is considered as a treatment option, many of these patients are heavily pre-treated and have acquired chemotherapy resistance and decreased BM reserve. However, the risk of unacceptable mortality is decreased by judicious patient selection and improvements in supportive care in transplantation, and increasing numbers of patients with advanced stage follicular lymphoma (FL), mantle-cell lymphoma (MCL) and CLL are now undergoing these procedures.

Correspondence to: John G Gribben, Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA © 2002 ISCT

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Although patients with indolent lymphomas respond to chemotherapy, conventional doses are not curative [2,3]. There has therefore been increasing awareness that novel treatement approaches are warranted for younger patients with more aggressive low-grade malignancies [4]. To date, no randomized study comparable to that performed for diffuse NHL has been performed in indolent lymphoma. There is increasing concern regarding toxicity of autologous SCT (autoSCT), especially the higher-than-expected long-term risk of development of myelodysplastic syndrome. This, associated with the decreased morbidity of non-myeloablative conditioning regimens, has led to renewed interest in the role of allogeneic SCT (alloSCT) for these patients. Issues to be addressed in low-grade lymphomas are shown in Table 2.

Source of autologous stem cells BM was previously used as the sole source of hematopoietic stem cells. Stem cells are mobilized into peripheral blood following chemotherapy, and this stem-cell mobilization is increased with concomitant use of hematopoietic growth factors, particularly with recombinant G-CSF. Sufficient stem cells for rescue following HDT can therefore be collected by pheresis of patients at fixed time-points after chemotherapy. Most patients now receive autologous PBSC, rather than BM. There are a number of advantages with using PBSC rather than BM. It is easier, cheaper and safer to collect stem cells by pheresis rather than to harvest BM. Mobilized PBSC hasten engraftment compared with BM. In a randomized prospective trial, use of PBSC rather than BM decreased the number of platelet transfusions, and time to

Table 1. Reasons why SCT has been rarely performed in low-grade lymphomas Long natural history of disease Fear of morbidity and mortality in patients who can remain alive with their disease for many years Older age at presentation High frequency of BM infiltration makes autologous SCT difficult Patients heavily pre-treated by the time SCT is considered an option.

Table 2. Transplantation for low-grade lymphomas Source of stem cells BM PBSC Timing of procedure In first remission After relapse Molecular monitoring of disease Contribution of contaminating lymphoma cells in the stem-cell collection to relapse Source of donor Autologous stem cells Allogeneic stem cells Immunologic manipulation of stem cells Biologic response modifiers GvL effect Autologous anti-lymphoma effect Generation of anti-lymphoma specific cells for adoptive immunotherapy

Autologous hematopoietic transplantation for low-grade lymphomas

neutrophil and platelet engraftment, resulting in an earlier discharge from hospital [5]. It has been suggested that mobilized PBSC contain fewer tumor cells than BM, but this issue has been very poorly studied. The majority of patients who have undergone autoSCT have had no evidence of disease infiltrating the BM. In a matched pair analysis from the European Group for Blood and Marrow Transplantation Registry Data [6], engraftment was faster using PBSC than BM. For patients with NHL there was no difference in long-term outcome, but patients with HD receiving PBSC had poorer disease-free and overall survival compared with those receiving SCT. Different methods for collection of PBSC are in use. When patients were randomized to PBSC mobilization using G-CSF alone compared with CY plus G-CSF [7], although higher numbers of CD341 stem cells were collected after chemotherapy plus G-CSF, there was no difference in time to engraftment between the two arms of treatement, and no difference in tumor contamination. This trial provides evidence that G-CSF alone is adequate for mobilization in the majority of patients, even when heavily pretreated. In low-grade lymphoma the rationale for the use of PBSC has been not only to hasten hematologic engraftment, but also because these stem cells are felt to be less contaminated with tumor. Of considerable interest with the use of PBSC is whether previous therapy with stem-cell toxic agents impairs the ability to mobilize progenitor cells, or impairs engraftment potential. This is of particular interest in the low-grade lymphomas that have often received prolonged therapy with alkylating agents. However, without the use of such therapy, there will be concern that the harvested stem-cell source will contain residual lymphoma cells that may contribute to subsequent relapse.

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Molecular monitoring of disease A major advantage of studying the indolent lymphomas is that they are often characterized by non-random chromosomal translocations that can be detected by PCR amplification (Table 3). In addition, in common with other B-cell malignancies, low-grade lymphomas undergo clonal-specific rearrangement of the immunoglobulin gene loci. One of the most widely studied chromosomal translocations is t(14;18), which occurs in 85% of patients with FL and 30% of patients with diffuse lymphoma. In t(14;18) the bcl-2 proto-oncogene on chromosome 18 is juxtaposed with the Ig heavy chain (IgH) locus on chromosome 14. The breakpoints have been cloned and sequenced [8–11]. The clustering of the breakpoints at these two main regions at the bcl-2 gene, and the availability of consensus regions of the IgH J regions, make this an ideal candidate for PCR amplification to detect lymphoma cells. Cells bearing the translocation have been detected in hyperplastic lymphoid tissue with no evidence of lymphoma [12,13] and in normal B-cells [14]. However, these cells are sufficiently rare not to interfere with the use PCR in the clinical management of patients who are being monitored for residual disease. The t(11;14) is associated with a number of B-cell malignancies, including B-cell CLL, myeloma, and in particular, in the majority of patients with MCL. In this translocation the proto-oncogene bcl-1 (also known as PRAD-1) on chromosome 11 is juxtaposed to the IgH chain locus on chromosome 14 and the breakpoints cloned and sequenced [15]. Although the breakpoints on chromosome 11 are widely scattered, the majority are clustered within the major translocation cluster (MTC), making it suitable for amplification by PCR [16,17]. At our

Table 3. PCR amplifiable chromosomal translocations and gene rearrangements low grade lymphoid malignancies Disease

Translocation

Genes involved

Lymphomas Follicular and diffuse NHL MCL

t (14; 18) t (11; 14)

bcl2–IgH bcl1–IgH

Gene rearrangements Immunoglobulin heavy chain

Diseases FL MCL CLL

JG Gribben

own center, autoSCT did not eradicate residual disease and did not improve outcome in MCL [18]. This suggests that the eradication of PCR-detectable lymphoma cells will be necessary for cure in this disease [19].

PCR detection of Ag-receptor gene rearrangements Although most FL exhibit t(14;18), and small subsets of patients have characteristic chromosomal translocations, the majority of patients with lymphoid malignancies do not demonstrate non-random chromosomal translocations. B-cell malignancies usually rearrange Ig genes, and their clonal progeny have this identical Ag-receptor rearrangement. The third complementarity-determining region (CDR III) of the IgH gene results from the rearrangement of germline variable (V), diversity (D) and joining (J) region elements. The final V-N-D-N-J sequence is unique to that cell and, if the cell expands to form a clone, then this region may act as a tumor marker. PCR amplification of the CDR III sequence is possible due to the presence of conserved sequences within the V and J regions, and strategies have been successfully applied to amplify the CDR III region. In neoplastic B cells there is non-random usage of VH families. In CLL there is a bias towards use of VH5 andVH6 [20], but in FL, VH gene usage appears to mirror that seen in normal peripheral-blood B cells, with a predominance of VH3 [21]. FL cells can also exhibit an oligoclonal pattern and, characteristically, have heavily mutated V genes [22].

Monitoring minimal residual disease after SCT PCR analysis has been performed on serial BM samples obtained after autoSCT to assess whether HDT might be capable of depleting PCR detectable lymphoma cells [23–25]. Failure to achieve or maintain a CR, as assessed by PCR analysis of BM, appears to be predictive of which patients will relapse. The results of these studies suggest that detection of minimal residual disease (MRD) by PCR following autoSCT in patients with lymphoma identifies those patients who require additional treatement for cure, and also suggests that our therapeutic goal should be to eradicate all PCR-detectable lymphoma cells. The results of PCR analysis of patients who have undergone autoSCT at Dana-Farber Cancer Institute are shown in Figure 1. Three groups of patients are identified. Those patients who have no PCR evidence of

disease (PCR neg) have a very good prognosis. In contrast, patients who have persistence of PCR-detectable disease at all time-points after SCT (PCR pos) have a very poor outcome. The third group of patients had a mixed response, with PCR-detectable disease at some time-points after SCT. These patients had an intermediate prognosis. PCR therefore identified two patients at high risk of relapse, those patients who had persistence of PCR-detectable disease and those patients who had re-appearance of PCR-detectable disease. Although, these results were not confirmed in one study [26], they have been confirmed by others [25,27]. It is becoming increasingly clear that qualitative assessment of PCRdetectable disease may not be sufficient to determine outcome after SCT. Real-time PCR analysis is a technique that now allows quantitative assessment of disease and is being applied increasingly to evaluation of patients with B-Cell malignancies [28]. HDT is also capable of eradicating PCRdetectable disease in CLL [29,30]. Although it is encouraging that SCT appears capable of eradicating minimal residual leukemia cells, the number of events in these studies are, as yet, too small to adequately assess the impact of eradication of MRD in this disease.

Contribution of re-infused lymphoma cells to relapse after autoSCT The major obstacle to the use of autoSCT is that the reinfusion of occult tumor cells harbored within the BM may result in more rapid relapse of disease. A variety of methods have therefore been developed to ‘purge’

% disease free survival

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100 PCR neg (158; 7 relapses)

80 60

PCR mixed (115; 32 relapses)

40 20 0

PCR pos (119; 73 relapses)

0

2

4

6

8

10

12

14

16

Years after ABMT

Figure 1. Results of PCR analysis of serial BM samples obtained in remission following autoSCT for patients with low-grade NHL undergoing autoSCT at Dana-Farber Cancer Institute. PCR neg. 5 no PCR detectable disease in any samples. PCR mixed 5 PCR detectable disease at some time-points after autoSCT. PCR pos. 5 PCR detectable disease found in all samples obtained after autoSCT.

malignant cells from the BM. The aim of purging is to eliminate any contaminating malignant cells, and leave intact the hematopoietic stem cells that are necessary for engraftment. The development of purging techniques has led subsequently to a number of studies of autoSCT in patients with either a previous history of BM infiltration, or even overt BM infiltration at the time of harvest [31]. MAbs are ideal agents for selective elimination of malignant cells because of their specificity. PCR amplification of the t(14;18) was used to detect residual lymphoma cells in the BM before and after purging in patients undergoing autologous BM transplantation, to assess whether the efficiency of purging had any impact on DFS [32]. The incidence of relapse was significantly increased in the patients who had residual detectable lymphoma cells compared with those in whom no lymphoma cells were detectable after purging. This finding was independent of the histology of the lymphoma, the degree of BM infiltration at the time of BM harvest, or remission status at the time of autologous BM transplantation. An updated follow-up of these patients continues to show a significantly improved DFS of patients who are re-infused BM with no residual PCRdetectable lymphoma cells (Figure 2). Similar results have been obtained in other studies. In a study to evaluate the prognostic significance of detection of MRD, 65% of patients with low- or intermediate-grade NHL had PCR-detectable t(14;18) in their BM or peripheral blood [33]. Twenty-nine of 52 patients studied were transplanted with a PCR-positive graft. The likelihood of obtaining a PCR-negative graft was higher when patients were transplanted in first remission. Patients who received a PCR-negative graft are faring better than those patients who received a graft that contained PCR detectable disease. The clinical significance of detection of MRD at the time of collection of autologous BM, and in the patient after therapy, was also assessed by PCR-amplification of clonal-specific IgH rearrangements [24]. In this study, eradication of PCRdetectable residual disease after purging was also associated with improved outcome, and persistance of PCR-detectable disease in the patient also adversely affected prognosis. In patients with MCL, immunologic purging was largely unsuccessful in eradicating PCRdetectable lymphoma cells [19]. Immunomagnetic bead depletion can also be used as a tumor-free source of stem cells in both FL and MCL [34].

% disease free survival

Autologous hematopoietic transplantation for low-grade lymphomas

209

100

PCR negative purging (115 patients, 14 relapses)

80 60

p < 0.0005

40

PCR positive purging (57 patients, 54 relapses)

20 0

0

2

4

6

8 10 Years

12

14

16

Figure 2. Results of PCR analysis of autologous BM after immunologic purging. These results are a 10-year update on a cohort of patients reported initially in 1991 [30].

Secondary leukemia after SCT A major complication of autoSCT is the development of therapy-related myelodysplastic syndromes (MDS) and secondary AML. The actuarial risk of developing therapyrelated leukemia (t-MDS/AML) after autoSCT for lymphoma is substantial. As shown in Table 4, the actuarial risk varies between centers, ranging from 3% to as high as 24% of patients [35–43]. The incidence of development of MDS, as a complication after autoSCT for lymphoma, in 552 patients who had undergone autoSCT for NHL between 1982 and 1997 at Dana-Farber Cancer Institute was recently reviewed [42]. Following relapse of disease, development of secondary MDS or acute leukemia has emerged as the second most common cause of death in these patients. Attempts are being made to evaluate the role and validity of genomic-wide loss of heterozygosity (LOH) screens, quantitative PCR for specific mutations and gene rearrangements, and assessment of global expression patterns to identify signatures predictive of MDS/AML [44].

SCT for FL Historically, fewer patients with FL have undergone SCT. However, this procedure can be performed in patients with FL who have previously relapsed with low mortality [31]. Studies at Dana-Farber Cancer Institute focused on this population as a model to assess the importance of immunologic purging of residual tumor cells [32]. Purging has also been performed in this patient population in Stanford [45]. In this series, patients treated with TBI-containing conditioning regimens had improved overall and DFS. The feasibility of using non-purged PBSC was assessed in 60 patients with poor-prognosis FL [46]. Twelve of these patients were treated in first PR, and the vast majority were in second or greater CR or PR.

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Table 4. Actuarial risk of t-MDS/AML after autoSCT Institution

Year

Acutarial risk (%)

Minnesota City of Hope Nebraska Dana-Farber Copenhagen French Cooperative British Cooperative EMBT Cooperative

1996 1998 1994 1999 1997 1998 1999 1999

13 9 4 20 24 4 3 5

/6 years /9 years /5 years /10 years /43 months /5 years /5 years /5 years

Adapted from Pederson-Bjergaard et al. [41].

Seventy percent of these patients had BM infiltration at the time of treatment. The treatment-related mortality (TRM) was 8%, and in most cases was associated with prolonged time to engraftment. Complications occurred more frequently in more heavily pre-treated patients. Estimated DFS at 2 years was only 53%, but there was a relatively short median follow-up of 21 months. Patients treated in first or second PR or second CR had significantly improved outcome compared with patients treated with progressive disease. In another prospective study, 48 patients with low-grade NHL received PBSC transplants [47]. In this study, 28 patients were treated in first remission, seven in second or higher remission and 20 patients were treated in relapse. There was low TRM. Only seven patients relapsed, although the median follow-up at only 15 months is very short. The data remains controversial that patients with FL have the best outcome when they are treated relatively early in their disease course, and at a time when they have little tumor bulk. SCT in first remission in highrisk patients with FL was addressed in a study using mafosfamide-purged BM [48]. The outcome for patients treated with SCT was significantly better than that of historical controls although there is considerable selection bias in this patient population and there are problems inherent in the use of such historical controls. In a pilot study from the Dana-Farber Cancer Institute, 78 patients in first CR/PR were treated [49]. This study enrolled patients on an ‘intent to treat basis’ and suggested that virtually all patients with FL can achieve minimal disease state before proceeding to autoSCT. There was, however, no difference in event-free survival after SCT

for those patients treated in first remission compared with those treated in sensitive relapse. Even in studies where there is apparent improvement in the response rate, this may not lead to improved longterm survival [50]. However, 37 patients with FL at Stanford were enrolled in a Phase II study and, after receiving conventional chemotherapy, received consolidation therapy with TBI and high-dose etoposide and cyclophosphamide and SCT [51]. Outcome was compared with a reference population of patients treated at Stanford without receiving SCT. With a median followup of 6.5 years, the estimated overall survival of patients undergoing autoSCT was 86%, which compared favorably with historical controls. Patients whose disease has undergone previous histologic transformation, whose transformation occurs early in their disease course, and whose disease remains chemosensitive, may experience prolonged survival after autoSCT [52,53]. These findings from single center studies were confirmed in analysis of registry data from the European Bone Marrow Transplant Group. There was no difference in outcome for patients with chemosensitive transformed disease compared with those with FL or de novo diffuse large-cell lymphoma [54].

SCT for MCL The role of HDT and autoSCT in MCL remains unproven. Although promising results have been seen in some studies using HDT and SCT in this disease, followup is often short [55,56]. At Dana-Farber Cancer Institute, autoSCT using B-cell purged sources of stem cells was associated with a high response rate and early promise,

Autologous hematopoietic transplantation for low-grade lymphomas

but there was a high probability of relapse with DFS of only 31% at 4 years with no evidence of a plateau [18]. Similar results were obtained at the University of Nebraska Medical Center; with a median follow-up of only 2 years, event-free survival was 36% [57], and at Lyon with event-free survival at 3 years of 24% [58]. High response rates have been seen in this disease using the hyper-CVAD regimen, with promising results observed using HDCT and SCT as consolidation therapy in this patient population [59]. Aggressive up-front therapy may be necessary, and promising results have also been seen using the Dexa-BCNU–etoposide–cytarabine–melphalan (Dexa-BEAM) regimen prior to HDT approaches in this disease [60,61]. Of note, molecular monitoring revealed that in this disease setting we almost never observed eradication of PCR-detectable disease in the autologous BM collection [19]. PSBC may be less contaminated in this disease setting [25]. Use of in vivo purging using humanized MAbs may also be capable of eliminating contaminating MCL cells from the PBSC collection [62].

SCT for CLL In CLL it is important to maintain a balance between the risk of a procedure and the risk of dying from the disease. The decrease in morbidity and mortality that have resulted from improvements in SCT procedures and supportive care have therefore led to an increase in the use of SCT in CLL—often with promising results. Moreover, the identification of patients with CLL who have sufficiently poor prognosis to merit more experimental treatment approaches with curative intent, is of crucial relevance with regard to the morbidity and mortality risks of this procedure. At Dana-Farber Cancer Institute, SCT has emerged as the treatment of choice for younger patients with poor prognosis CLL. Studies investigating the role of SCT in this disease have been ongoing since 1989, and have focused on the use of autologous compared with allogeneic SCT. The treatment approach for younger patients with poor-risk features is shown in Figure 3. To be eligible for autoSCT such patients must achieve a protocol-eligible low disease burden, following induction or salvage therapy, with largest nodal masses ,2.5 cm, BM involvement ,20% and no splenomegaly. Patients with high-risk CLL who achieve a protocol-eligible low tumor burden state have been offered alloSCT if they have an HLA-matched sibling donor. If no suitable HLA-matched sibling donor

211

High risk CLL £65 years

Protocol-eligible low tumor burden

No protocol-eligible low tumor burden

Cytoxan 60 mg/kg for 2 days Fractionated TBI to 1400 cGy

HLA-matched sibling donor

No HLA-matched sibling donor

AlloSCT

AlloSCT T-cell depleted with anti-CD6

AutoSCT purged with anti-B cell MAbs

HLA-matched sibling Matched unrelated Mismatched sibling

Figure 3. Approach to SCT for CLL patients with high-risk clinical features at Dana-Farber Cancer Institute.

is available, patients receive B-cell purged autoSCT. Results to date have demonstrated an improved overall and event-free survival advantage of autologous compared with allogeneic BMT, because of the higher TRM associated with GvHD in patients undergoing allogeneic BMT. Those patients who do not achieve a protocol-eligible disease state are still eligible for alloSCT, either from matched sibling donors or from unrelated donors. The outcome of these two latter groups of patients are not compared with those patients who have undergone autoSCT, since these patients are taken to SCT with a larger tumor burden and without demonstrated chemosensitivity of their disease. To date, almost 200 patients have now undergone autoSCT for CLL. Treating patients with chemosensitive disease at a time of achieving a minimal disease state appears to be associated with a low treatment-related mortality, ,5%. With a median follow-up of .4 years, the 5-year estimated overall survival for these patients is .80%, with event-free survival estimated at 65%. In this study, a number of patients with heavily pre-treated poor prognosis CLL have now remained disease-free for .10 years following autoSCT. Patients with poor prognosis CLL in first CR or PR became eligible for consideration of this approach in 1994. These patients are demonstrating excellent DFS to date, but clearly further follow-up will be required to determine whether autoSCT in this setting improves outcome in CLL.

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CLL is therefore one disease setting in which the role of autoSCT versus alloSCT has been addressed [30,63–65]. Although both autoSCT and alloSCT are capable of eradicating MRD, the likelihood of achieving such eradication of MRD was higher following alloSCT than autoSCT [30]. The largest reported series of patients receiving SCT for CLL is from a retrospective analysis of registry data [66]. Fifty-four patients who have undergone HLA-matched sibling donor SCT at 30 centers were identified. Before this procedure is more widely accepted in this disease, the treatment-related morbidity and mortality would have to be improved. In the registry data, the TRM was unacceptably high, at 46%. However, for those patients surviving the procedure, response rates were high. In view of the fact that the majority of patients are more elderly, the disease appears ideal to consider.

Immunological manipulation after SCT Patients who relapse after SCT for NHL do so because of the persistence of small numbers of lymphoma cells that survive HDCT. Eradication of such ‘minimal residual’ disease migh be mediated by immune recognition of these lymphoma cells by the host immune system. One particular problem with this approach is that the host immune system is severely compromised by the SCT procedure itself. However, a number of studies (reviewed in Reference 67) have addressed whether the use of biologic response modifiers, particularly IL-2, might improve immune recognition of lymphoma cells after SCT. It is difficult to determine from the published studies whether the use of IL-2 after SCT has led to any improvement in outcome. The major potential advantage of the use of alloSCT, rather than autoSCT is the potential for a graft versus tumor effect. In the same way that donor T cells can recognize the host and induce GvHD, they are also capable of recognizing host tumor cells. A novel approach is to combine HDCT approaches with immune recognition of tumor cells, by vaccination with idiotype protein post-autoSCT. Using this approach in patients with FL immune responses has been documented in 10 of 12 patients [68].

AutoSCT versus alloSCT in low-grade lymphoma The role of alloSCT in low-grade malignancies has been studied even less, and is discussed elsewhere. The issue of whether an individual patient should be considered a

candidate for autoSCT versus alloSCT is an important and often difficult to decision to make. Although alloSCT is associated with increased morbidity and mortality, it remains a potentially curative procedure that provides a tumor-free source of stem cells that may ultimately allow assessment of whether there is a graft versus tumor effect in these diseases. There are few reports demonstrating any advantage of autoSCT over alloSCT in low-grade lymphoma [69]. There are, however, a number of reports of patients from single centers, suggesting that durable remission can be obtained following alloSCT in the low-grade lymphomas [63,64]. In a retrospective analysis of 64 patients with endstage NHL who have undergone allogeneic BMT, patients with low-grade lymphoma had significantly improved outcome compared with patients with intermediate- and high-grade NHL [70]. It was concluded that alloSCT is an effective procedure that can result in long-term remission in patients with refractory low-grade NHL [71].

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