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Review article: Autologous Stem Cell Transplantation: Indications and Results

Last update: 02/09/2006

Deciding if SCT is indicated (and when) is probably one of the more difficult treatment decisions we can make for follicular NHL.  The following is a review article on the subject intended for oncologists.   We've divided the text to make it a bit more readable.  It covers both allo and auto types, including mini.  Feel free to comment (always) or ask questions.   I've marked the author's conclusion statements with double **
Autologous Stem Cell Transplantation: Indications and Results
(autologous means stem cells from patient)
from review article ASH 2004:

To see the tables you most go to the source document (the link above).

Although ASCT (also abbreviated alloSCT) in follicular NHL has been studied most extensively in the treatment of patients with recurrent disease, it also has been used as consolidation of first remission and in the treatment of patients with *transformed* lymphoma.

ASCT for recurrent disease

Chemotherapy at conventional dose for the treatment of patients with recurrent follicular NHL is likely to produce consecutive remissions of shorter duration each time. Several Phase II studies suggest, however, that salvage treatment followed by consolidation with ASCT can result in prolonged disease-free survival (DFS).1;2

Freedman and colleagues reported the largest single institution experience. A total of 153 patients were treated with ASCT using autologous bone marrow purged in vitro with anti-B cell monoclonal antibody.

At a median follow-up of 5 years (range 2-13 years), the estimated 8-year DFS and OS were estimated as 42% and 66%, respectively.3

Table 2 lists other major Phase II trials that showed similar results using different hematopoietic cell sources, purging methods, conditioning regimens, and follow-up periods.
All trials suggested an improved median duration of progression-free survival (PFS) compared to historic controls treated with conventional chemotherapy and prolonged PFS in a fraction of patients.

On the other hand, with prolonged follow-up, recurrence rates of over 50% were generally observed and questions remain as to whether the durable responses were due to a treatment effect versus patient selection.

The European Bone Marrow Transplantation Registry (EBMTR)-sponsored CUP trial (conventional Chemotherapy, Unpurged autograft, Purged autograft) conducted between 1993 and 1997 is the only prospective randomized trial to address the role of ASCT in prolonging PFS and overall survival in patients with follicular NHL.4

Due to slow accrual, the trial was closed after enrollment of 140 of a planned 250 patients. Sixty-five percent of patients were in first relapse, the remainder in subsequent relapses.

Patients were given three initial cycles of chemotherapy (usually a CHOP-like regimen), and 89 patients who attained at least a partial response were randomized to one of three treatment arms:
1) further conventional chemotherapy,
2) ASCT using purged autografts or
3) ASCT using unpurged autografts.
Too few patients were entered to assess the effect of ex-vivo purging.
PFS and OS at 2 years after transplant for both patient groups randomized to ASCT were 55% and 71% compared to 26% and 46% for those receiving conventional hemotherapy, respectively.
Hazard ratios for survival and PFS were 0.3 and 0.4, respectively, when comparing conventional chemotherapy with ASCT.
These data are highly significant statistically and demonstrate that **ASCT provides an important survival benefit in patients with chemosensitive recurrences of follicular NHL** and should currently be considered a treatment of choice in this situation.

ASCT as consolidation of first remission

ASCT has also been used for low-grade NHL patients in first complete or partial remission in order to prolong or render such remissions permanent.
Several Phase II trials are summarized in Table 3.

Most of them found very prolonged PFS in a substantial proportion of patients and favorable outcomes compared with historical controls. This led several groups to develop multicenter, randomized studies comparing ASCT consolidation versus IFN maintenance or observation.

The German Low Grade Lymphoma Study Group randomized patients younger than 60 years of age with chemosensitive indolent NHL (mostly follicular NHL) in first partial or complete remission to ASCT versus maintenance interferon therapy.5 Two hundred forty patients with FL were evaluable for the comparison of ASCT versus IFN maintenance.

At a median follow-up period of 4.2 years, 31 relapses (27.2%) were observed in the ASCT study arm and 76 relapses (60.3%) in patients receiving IFN maintenance. In addition, 5 deaths occurred in remission (4 patients in the ASCT study arm and 1 in the IFN group). Accordingly, the PFS was significantly different in the two study arms.

In patients receiving ASCT, the PFS was 79.1% after 2 years (95% confidence interval 71.4% to 86.9%) and 64.7% after 5 years (95% confidence interval 54.6% to 74.8%) ...
... in comparison to only 52.7% (95% confidence interval 43.8% to 61.7%) after 2 years and 33.3% (95% confidence interval 24.3% to 42.3%) after 5 years in the IFN study arm respectively (P < 0.0001).

The French Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM) group also reported in preliminary fashion that ASCT decreased recurrence rates but **did not have any effect on long-term survival**.6
This may be due to the fact that patients undergoing ASCT appeared at increased risk for the development of myelodysplastic syndrome (MDS). In the absence of a demonstrated survival benefit, **we do not routinely recommend ASCT in first remission for follicular NHL patients**.

=Technical Considerations

Several technical aspects of ASCT such as method of stem cell collection, ex vivo purging [outside the body], conditioning regimen, and aspects of supportive care may have a considerable influence on the outcome of transplant and ideally should be investigated in randomized studies.

For a variety of reasons these aspects of care generally have not been addressed in this fashion. **Definitive answers to questions of the optimal preparative regimen or optimal stem cell sources therefore are not possible.** Some recommendations can be provided by comparison of individual study results, case-control studies and perhaps best from multivariable analysis of large observational data sets.

=Conditioning (treatment given to ablate immune system)

Transplant conditioning regimens for ASCT in follicular NHL can be
classified into three variants:
1) total-body irradiation (TBI)-containing;
2) high-dose BCNU-based (BEAC, BEAM, CBV); and
3) busulfan-based (BuCy, BuEtoposide).

Largely for historic reasons, TBI-containing or BCNU-based regimens are used most commonly in follicular NHL. An IBMTR analysis indicated that use of TBI might be associated with an increased treatment-related mortality (TRM).7

On the other hand, TBI in the preparative regimen was also associated with decreased rates of disease recurrence.
This observation, while far from definitive, suggests that TBI is a particularly effective but rather toxic treatment for FL and provides a **rationale for the further development of radiolabeled monoclonal antibodies as part of conditioning regimens for transplant.**
A Phase II study of I131-labeled anti-CD20 (tositumomab) combined with high-dose chemotherapy suggests an improved overall survival compared with historical controls receiving TBI.8


Most patients with follicular NHL present in advanced disease stage and often with morphologic evidence of marrow involvement. Even in patients with histologically normal marrow, occult marrow involvement usually can be demonstrated by PCR.
Further, occult [too small to see] lymphoma cells contaminating the stem cell infusate likely contribute to relapse after autologous transplantation. 
Ex vivo technologies to decrease tumor contamination include 'positive' selection (i.e., the in vitro enrichment of the graft for CD34 cells, a marker presumably lacking on lymphoma cells) as well as 'negative' selection (i.e., the removal of tumor cells by exposure to lymphoma-specific antibodies).

The group from the Dana Farber Cancer Institute found that successful in vitro [out side body] purging was associated with dramatically improved freedom from relapse in follicular NHL patients undergoing ASCT.3
Furthermore, Ladetto et al showed that successful in vivo purging (i.e., the generation of PCR-negative harvests after intensive induction chemotherapy) was associated with improved PFS.9 Fouillard et al, by using various purging methods, also found a correlation between graft purging and outcome.10
Only one group failed to find a correlation between PCR status of the infusate and recurrence.11

The obvious corollary of these findings is that occult lymphoma cells contribute to recurrence in tumor-contaminated grafts. However, the absence of a control group makes it impossible to rule out the alternative explanation, namely that the ability to achieve a tumor-free graft is a surrogate for chemotherapy sensitivity.

The CUP trial attempted to address this issue in a prospective fashion, but low patient numbers limited the study's power. Indirect evidence of the role of a tumor-free graft comes from registry analysis.
In an IBMTR study of follicular NHL, stem cell purging was identified as an independent predictor for PFS and OS.7
Also a case-control study by Bierman et al showed that syngeneic transplants had a lower recurrence rate than purged autologous transplant, which in turn had a lower recurrence rate than unpurged autologous transplant.12
We interpret these data as indicative of the importance of providing a tumor-free graft. Current technology limits the efficacy of graft purging and further research in this area is indicated. Recently, rituximab has been used as an "in vivo [in the body] purging agent."13

Pilot studies indicate that rituximab administration eliminates PCR-detectable cells in a significant proportion of hematopoietic cell harvests but may be associated with late neutropenia and serious infection.14 Whether transplant outcome will be improved by collecting PBSC after exposure to rituximab remains to be demonstrated.

=Late toxicities of ASCT

Although early morbidity is considerable, advances in supportive care have significantly reduced the immediate TRM associated with ASCT, even in elderly patients.
On the other hand, late treatment-related side effects, such as MDS or secondary acute myeloid leukemia (sAML) occur with a 5- to 15-fold increased incidence.15,16
The etiology [how it evolves] of posttransplant MDS is complex and relates to a combination of host-related factors, prior treatment, and conditioning. The outcome for patients who develop treatment related MDS/AML usually is very poor.

Allogeneic Stem Cell Transplantation
(stem cells from from donor)

=Myeloablative transplantation

The exact role of allogeneic stem cell transplant (alloSCT) in follicular NHL remains somewhat difficult to define (Table 4).
Allotransplant initially was used in patients thought not to be candidates for ASCT due to extent of disease or marrow involvement.

Several retrospective studies suggest that alloSCT is associated with a very low relapse rate and might be a curative treatment for FL.

On the other hand, the benefit of alloSCT was offset by high TRM (treatment related mortality).
The IBMTR reported data on 904 follicular NHL patients who underwent either ASCT or alloSCT between 1990 and 1999.7

A total of 176 (19%) received alloSCT, 131 (14%) received purged ASCT, and 597 (67%) received unpurged ASCT.

* The 5-year TRM rates were 30%, 14%, and 8%

* Recurrence rates were 21%, 43%, and 58% after alloSCT, purged ASCT, and unpurged ASCT, respectively.

*  Furthermore, the 5-year probabilities of survival were 51%, 62%, and 55%  after alloSCT, purged ASCT, and unpurged ASCT.

This communication confirms the high TRM yet low recurrence rate with alloSCT and overall similar long-term survival compared to patients undergoing ASCT.

These **data do not allow practitioners to make decisions for the use of alloSCT versus ASCT, and treatment recommendations continue to be guided by physician judgment.**

Over the past decade, advances in supportive care and better patient selection have resulted in improved outcomes for alloSCT. Also, the risk of secondary MDS after alloSCT is negligible. We currently ** recommend alloSCT for recurrent NHL patients under age 50 years who have an HLA-identical sibling.**

Use of a TBI-based conditioning may be preferred due to the decreased recurrence rate associated with that modality.

=Reduced-intensity transplantation (mini)

Reduced-intensity conditioning regimens, considered less toxic, are being used increasingly often (Table 5).

The underlying hypothesis of such a strategy is that fewer patients will develop TRM and graft-versus-leukemia (GVL) effects will be effective in curing NHL.
Interesting preliminary results indicate that this premise may be the case,17 and the potency of GVL effects is underscored by the sometimes spectacular responses to donor lymphocyte infusion.18

Still, the **considerable risks and toxicity associated with chronic GVHD cannot be underestimated.**19

Paradoxically some of the best reported results involve in-vivo or in-vitro T cell-depleted transplants.20

Also, there is a certain arbitrariness to the definition of "reduced intensity" and a plethora of conditioning variants that renders interpretation of data difficult. The value of reduced-intensity alloSCT hopefully will be answered by a recently activated trial conducted by the Blood and Marrow Transplant Clinical Trials Network comparing ASCT versus
alloSCT in follicular NHL patients.
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For all medical concerns,  you should always consult your doctor. 
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