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Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma

Hematopoietic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma

For clinicians, the most practical
way to approach the treatment
of non-Hodgkin's lymphoma
is based on the clinical behavior
of the disease. Hematopoietic
stem cell transplantation (HSCT) has
been the backbone of the therapeutic
options for treating aggressive (intermediate-
and high-risk) disease that
has relapsed or does not respond to
initial therapy. Its role in the treatment
of indolent lymphomas has been
more commonly applied in patients
with multiply relapsed or refractory
disease. In some cases, such as chemotherapy-
sensitive, relapsed aggressive
NHL, HSCT results in a durable
remission and is superior to conventional
salvage therapy.[1,2] There
may be a role, however, for an earlier
HSCT in patients with poor prognostic
factors at the time of initial
diagnosis. In this review, we will summarize
the treatment of indolent and
aggressive NHL with HSCT and comment
on the evolving role of new
hematopoietic stem cell transplant-
based therapies.

Indolent Non-Hodgkin's
Lymphoma

The role of HSCT in treating indolent
lymphoma has been limited
not only by the heterogeneity of the
disease and its chronicity with many
long-term survivors, but also by high
rates of transplant-related mortality
with allogeneic HSCT and high rates
of relapse after autologous HSCT.

Autologous Transplants
Autologous transplants in this
setting have an observed regimenrelated
toxicity rate that is similar to
that seen with other HSCT-treated
diseases. In most cases, the regimenrelated
mortality rate is about 5% to
10%. However, most published studies
report a continual relapse rate with
no obvious plateau in the survival
curves. Thus, autologous HSCT is
not curative therapy for the majority
of indolent lymphomas treated with
current regimens.[3,4] Relapses are
thought to be due to both the inability
to eradicate the tumor cells and tumor contamination of the infused
stem cell product.

In Vitro Purging in
Autologous Transplantation

Numerous groups, including
Freedman et al,[5] have reported that
patients who receive autologous
grafts that are not contaminated with
lymphoma cells by polymerase chain
reaction (PCR) analysis have a statistically
higher initial disease-free
survival rate, compared to patients
with PCR-contaminated stem cells.
As a result, considerable effort has
gone into studying the best way to
purge grafts of tumor contaminant
cells. The earliest such studies centered
on positive selection of CD34
cells. Other approaches have focused
on tumor elimination by antitumor
antibodies and complement or chemotherapy
exposure with drugs such
as 4-hydroperoxycyclophosphamide
or mafosfamide.

Initially, improved disease-free
survival was reported in patients who
underwent autologous bone marrow
purging with a cocktail of anti-B cell
monoclonal antibodies.[6] Greater
than a 3 log depletion of follicular
lymphoma cells was achieved, and
no lymphoma cells could be detected
in 50% of treated patients. Patients
who had PCR-detected residual lymphoma
cells in their stem cell product
were initially more likely to
relapse posttransplant, with a relapse
rate of 39% (vs 5% in PCR-negative
patients) after a median follow-up of
23 months (P In Vivo Purging in
Autologous Transplantation
Recently, interest has focused on
in vivo purging. Antibodies such as
rituximab (Rituxan), given prior to
high-dose chemotherapy, appear to
increase the sensitivity of lymphoma
cells to chemotherapy. Rituximab has
been studied by numerous investigators,
in many cases administered with
mobilization regimens for collecting
peripheral blood stem cells (PBSC)
in mantle cell and indolent NHL
patients.[10-12]

In a small pilot study, Magini et
al[11] showed that 93% of patients
receiving rituximab with chemotherapy
had a PCR-negative stem cell
graft, compared to 40% of control
cases. When granulocyte colonystimulating
factor (G-CSF, Neupogen)
alone is used for mobilization
of PBSC with rituximab, two or more
doses of rituximab should be given
before PBSC collection to get the
least contaminated product. Thus,
several groups have shown that rituximab
can render a stem cell product
free of contaminating tumor cells
by PCR while having no adverse effects
on the collection of an adequate
number of stem cells or on engraftment
posttransplant.

Rituximab has also been administered
post-HSCT. Brugger et al[13]
treated patients with follicular and
mantle cell NHL with four weekly
doses of rituximab after autologous
HSCT. Following total-body irradiation
and high-dose chemotherapy, the
complete response rate was 44%, and
after the addition of rituximab to the
transplant regimen, this rate initially
increased to 57% and continued to
improve over time. By 1 year, it was
88%, and by 2 years, all follicularNHL patients and 90% of mantle cell
lymphoma patients were in complete
remission. Following high-dose therapy,
48% of evaluable patients had
no evidence of disease by PCR. Immediately
after rituximab therapy,
this parameter improved to 80%, and
at 6 months posttransplant, it was
100%. Leukopenia and infections
were reported.

Horwitz et al[14] studied the administration
of rituximab alone posttransplant
in more aggressive NHL
or transformed B cell NHL, reporting
grade 3/4 neutropenia in 9 of 20
patients. Flinn et al[10] also reported
late infection problems, with three
deaths in the first year posttransplant
as well as neutropenia, disseminated
herpes zoster, and atypical mycobacterial
infections.

Thus, rituximab therapy appears
to be deliverable with good results in
this setting. However, increasing evidence
suggests that some patients
(at least 25% to 45%)[10,13,14] also
develop transient neutropenia after
transplant, and there may be an increased
risk of infection. Randomized
controlled studies of rituximab
use in an autologous transplant setting
are lacking. In the future, other
antibodies such as CD22 and CD40
will be similarly studied. It may be
that the most effective therapy will
involve a combination of antibodies,
similar to what has been reported for
in vitro purging.

Targeted Therapy in
Autologous Transplants

Another area of active research
has been to give targeted therapy, ie,
using radiolabeled antibody, combined
with chemotherapy and followed
by autologous stem cell rescue.
This targeted radiotherapy is based
on the fact that hematologic malignancies
are sensitive to radiation. In
addition, the antibody is not internalized,
nor does it need to activate an
immune response to generate an antitumor
effect. Based on the isotope
tagged to the antibody and its penetration,
the radiolabeled antibody
does not need to reach every malignant
cell for it to be effective.

Different radiolabeled antibodies
to anti-CD20 have been used in an autologous transplant setting.[15-19]
In a phase I/II study of iodine-131
tositumomab (anti-CD20, Bexxar),
etoposide, and cyclophosphamide
(Cytoxan, Neosar), Press et al[17] reported
that the maximum tolerated dose
of the anti-CD20 monoclonal antibody
was 25 Gy, with etoposide, 60 mg/kg,
and cyclophosphamide, 100 mg/kg.
The reported time to engraftment and
toxicity data were similar to historical
results with total-body radiation, etoposide,
and cyclophosphamide therapy.
Overall survival at 2 years was
83%, and the progression-free survival
rate at 2 years was 68%. Approximately
21% developed a human
antimurine antibody. The results have
been encouraging, but which radioisotope
and regimen will prove to be the
most effective and practical to deliver
remains unknown.

Many of the radiolabeled antibody
studies published to date have been
restrictive in their eligibility requirements,
for example, requiring no
evidence of enlarged spleen and low
tumor burden of no more than
500 cc. Randomized studies are needed
to show an increased benefit in
patients, for example, with increased
survival and disease-free survival
associated with the radiolabeled antibody-
containing regimens. Longterm
follow-up is also needed to
address the issue of whether secondary
malignancies are more likely to
occur with intensified radiolabeled
targeted therapy.

Unique Problems With
Autologous Transplant

Unique issues arise with respect
to transplanting low-grade lymphoma.
Fludarabine (Fludara) is commonly
used as conventional therapy
to treat the disease, and its use may
affect the ability to mobilize stem
cells.[20] Autologous transplants are
also problematic in this setting, given
the high rate of secondary cancers
reported, including myelodysplastic
syndrome (MDS)/acute myelogenous
leukemia (AML), for which incidence
rates are as high as 20%.[9,21]

Timing of Autologous Transplant
Recently, investigators have
placed much emphasis on moving autologous HSCT up earlier in patients
with poor prognostic factors.
Colombat et al[22] treated 29 patients,
with 7 in first complete remission
at a median follow-up of 6 years.
The overall survival was 64%, and
the actuarial event-free survival was
55%. Tarella et al[23] treated 46 patients
with advanced low-grade NHL;
17 had small lymphocytic lymphoma,
29 had follicular lymphoma, and 10
also had histologic transformation.
Patients received tumor debulking by
two courses of APO (doxorubicin
[Adriamycin], prednisone, vincristine
[Oncovin], methotrexate, asparaginase
[Elspar], mercaptopurine [Purinethol])
and two courses of DHAP
(dexamethasone, high-dose cytarabine
[Ara-C], cisplatin [Platinol]),
sequential administration of highdose
etoposide, methotrexate, and cyclophosphamide
with stem cell
harvest, and high-dose mitoxantrone
(Novantrone) and melphalan (Alkeran)
with PBSC infusion. Ten follicular
lymphoma patients had ex vivo
purging of stem cells. At a median
follow-up of 4.3 years, the estimated
9-year overall survival was 84% and
progression-free survival was 45%.
Follicular lymphoma patients had
longer survival without evidence of
disease-59% vs 17% for small lymphocytic
lymphoma patients. These
results indicate that there may be
longer progression-free survival after
autologous transplant if it is part
of the up-front therapy.

Thus, we need to address the issue
of whether a randomized study should
be conducted in patients with intermediate
and high scores on the International
Prognostic Index (IPI) of risk
factors, comparing the addition of a
front-line autologous HSCT after conventional
therapy. Indeed, front-line
autologous transplant may be very
relevant for the long-term benefit of
patients. As oncologists, we tend to
treat patients with multiple cycles of
different therapeutic regimens and
have in the past relied heavily on
alkylating agents. As we treat patients
more intensely for longer periods
of time, we can expect to see
more secondary cancers-especially
MDS/AML. The use of autologous
transplant upfront and the decreasing use of multiple regimens of therapy
initially may prolong the time to the
development of MDS. If we conduct
such studies in the future, we need to
use molecular correlating studies (eg,
microarray assays) to help identify
patients that do benefit from upfront
transplants.

Immunotherapy and
Biologic Modifier Therapy
After Autologous Transplant

Indolent NHL may be a better target
for immunotherapy approaches, in
both autologous and allogeneic settings.
Several different approaches are
being used to study the addition of
immunotherapy to an autologous
transplant to reduce relapse rates.
These strategies include treatment
with immune stimulators such as
dose-intensive interleukin-2 (IL-2,
Proleukin) therapy,[24] IL-2-incubated
stem cells with sequential
IL-2,[25,26] and low-dose IL-2 with
or without rituximab.[27] In indolent
lymphoma, vaccination with idiotypespecific
vaccines after transplant is an
alternative approach to be further
studied. Again, no randomized studies
have shown evidence of efficacy
with immunotherapy in this setting,
but the randomized Southwest Oncology
Group study of dose-intense IL-2
after an autologous transplant is still
ongoing. Other biologic modifiers
such as bcl-2 antisense for maintenance
therapy after autologous transplant
also need to be investigated.

Myeloablative and
Nonmyeloablative
Allogeneic Transplants

Allogeneic transplants offer the
advantage of a "clean" stem cell product
and a graft-vs-lymphoma effect.
With a myeloablative allogeneic
transplant, there is the risk of developing
graft-vs-host disease (GVHD)
and a high regimen-related mortality
rate. International Bone Marrow
Transplant Registry data for myeloablative
regimens shows a transplantrelated
mortality rate of 40% to 50%,
with an event-free survival rate of
49%. The high regimen-related mortality
rate has limited the use of myeloablative
allogeneic transplants. It
should be noted, however, that there is a plateau in survival in these allogeneic
transplant recipients. Because
of the high associated upfront mortality
rate, myeloablative allogeneic
transplants have never shown a survival
advantage.

In particular, patients with a history
of multiple therapeutic regimens
also seem to have an increased risk
of complications. T-cell depletion or
antithymocyte globulin (Thymoglobulin)
therapy is being used by many centers to cut down on GVHD incidence,
but these approaches usually
result in higher replase rates and may
not be the answer unless further manipulations
of the stem cell infusion
allow us to safely and effectively separate
the cells that cause GVHD from
those that provide the graft-vs-lymphoma
effect.

The intent of myeloablative allogeneic
transplant is to use high-dose
therapy to help eradicate the underlying
disease, prevent graft rejection,
and produce a graft-vs-lymphoma
response to maintain disease control.
In indolent NHL, a graft-vslymphoma
effect is documented by
lower relapse rates after an allogeneic
transplant and by the evidence
of tumor control by infusion of donor
lymphocyte cells following a
myeloablative transplant. Thus, if the
risk associated with a myeloablative
allogeneic transplant can be lowered,
the lower risk for disease progression
may eventually lead to a superior
outcome. The source of donor
stem cells appears to make a difference
in initial mortality rates,
with PBSC being superior to bone
marrow.[28]

Alternatively, nonmyeloablative
transplants have been studied based
on the theory that the most important
part of an allogeneic transplant is the
donor cell graft-vs-lymphoma effect.
Khouri et al[29] treated 15 patients,
11 of whom had engraftment of donor
cells and 8 of the 11 who achieved
a complete remission. Five of six patients
(83.3%) with chemotherapysensitive
disease have survived,
compared with two of nine (22.2%)
with refractory or untested disease
(P = .04). Thus, patients with lower
tumor burden and chemotherapy-sensitive
disease may be more effectively
treated with a nonmyeloablative
approach and have the longest duration
of responses. However, caution
is needed in selecting patients for
nonmyeloablative therapy. In many
diseases, higher doses of radiation
and chemotherapy have been associated
with a reduced risk of relapse.[
30] Nonmyeloablative therapy
probably needs to be considered
mainly in patients with a diagnosis
that is very sensitive to the graft-vslymphoma effect, older patients, and
patients with comorbid medical problems.
Indolent NHL may be a good
target for reduced-intensity nonmyeloablative
allogeneic stem cell
transplant.[31]

Tandem transplants with autologous
transplant followed by nonmyeloablative
allogeneic transplant has
also been studied.[32] In one trial, 11
of 13 patients achieved a complete
response postallograft, including 9
patients with a partial response after
the autograft. Seven also received
additional donor lymphocytes. Seven
patients developed acute GVHD
(grade 2-4) and two developed chronic
extensive disease. Between 210
and 340 days postallografting, 2 patients
have relapsed, 10 are alive,
and 5 are in complete remission. Five
have died-two from GVHD and progressive
disease, two from GVHD
and infection, and one from disease
progression.

Chronic Graft-vs-Host Disease
Chronic GVHD will remain a
problem after a nonmyeloablative
transplant. It therefore behooves us
to remember that in a myeloablative
setting, significant chronic GVHD is
associated with a 50% nonrelapse
mortality rate.[33] The pathophysiology
of GVHD is poorly understood
and needs to be further studied. The
identity of the antigenic targets for
the immune reactive cells have not
been well clarified; nor is it clear
which populations of cells mediate
the ongoing immune responses seen
in chronic GVHD. In a coisogenic
murine model, T cells from donor
mice transplanted into mice with only
a three-amino acid difference in their
Dr molecule developed chronic
GVHD.[34]

Some investigators believe that
recipient alloantigens provide the
stimulus for the graft-derived T cells
that have already undergone selection
and maturation in the donor thymus
environment, causing GVHD.
Alternative explanations have included
flawed T-cell reconstitution, dominant
autoantigens driving the system,
and improper thymic selection of de
novo donor cells undergoing maturation
in the new host that does not result in tolerance. Many of our therapies
for chronic GVHD, though, only
control disease but do not delete the
pathogenic clone.

The incidence of GVHD appears to
be similar between nonmyeloablative
and myeloablative transplant recipients,
although long-term follow-up is
lacking.[35] Older patients have decreased
thymus function, and thus, as
we age we generate an environment
more conducive to the development
of chronic GVHD. The preferred
source for nonmyeloablative transplants
studies are PBSCs, which are
associated with a higher risk of developing
chronic GVHD, a longer disease
duration, and a greater amount of therapy
required to treat GVHD.[36] Also,
many nonmyeloablative transplants
depend on additional donor lymphocyte
infusions for disease control. In
general, 80% of patients who receive
donor lymphocytes and respond develop
GVHD. Better understanding of
graft selection and the mechanism of
chronic GVHD, as well as alternative
approaches to treating GVHD that do
not affect lymphoma control, are
needed.

Optimizing Allogeneic
Transplant Therapy

Interest is also beginning to focus
on optimizing immune responses
against lymphoma cells in an allogeneic
transplant. Numerous laboratories
are studying the generation of
minor histocompatible antigen-specific
clones to treat residual disease
after allogeneic transplant for a hematologic
malignancy. However, the
concept of using restricted antigenspecific
T-cell clones as effective
treatment after transplant may be
flawed. The reason that the graft-vstumor
effect is so prominent in an
allogeneic setting most likely is due
to its polyclonal recognition of tumor
cells that results in disease control.
Limited recognition of tumor
cells by antigen-specific clones will
most likely lead to escape of recognition
of the tumor cells by various
mechanisms, and will not result in
effective long-term disease control.

Further investigation of the ability
to amplify the polyclonal tumor
response after an allogeneic transplant,to prevent relapse and to determine
which patients require this intervention,
needs to be undertaken.
In addition, what is lacking in humans
is the ability to separate the
cells that cause GVHD from the cells
that cause a graft-vs-tumor effect, and
we need to study the differences in
the antigen recognition repertoire of
these cells.

Summary
The optimal therapy for indolent
lymphoma and the timing of various
transplant entities remains unclear. It
is conceivable that early autologous
transplant for patients with intermediate
and poor IPI risk factors may
maximize survival and quality of life,
with nonmyeloablative allogeneic
transplants being left to later, when
disease recurs. Quality of life in patients
with chronic GVHD is poorly
studied in the setting of nonmyeloablative
transplants, and for patients
with indolent NHL, quality of life is
more of an issue early in the disease
than disease eradication, thus making
this type of approach an interesting
one for investigation in future
randomized trials.

Indolent disease is more likely to
be a good target for nonmyeloablative
immunotherapy than aggressive
disease that will quickly outgrow the
ability of the immune system to control
it. How much bulky low-grade
NHL tumor burden patients can have
at the time of nonmyeloablative transplant
is still poorly defined, but common
sense and previous experience
would argue that chemotherapy-sensitive
disease and a lower tumor burden
are associated with the best
long-term outcomes.

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