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Autologous Stem Cell Transplantation: Indications and Results
(autologous means stem cells from
patient)
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
=Purging
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.
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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.
