2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

potential for GVL-mediated disease eradication does make it
an attractive option for patients with increasingly shorter
remission durations or young patients with relapsed disease
where the likelihood of decades of disease control with
currently available standard therapies is low. The associated
toxicities (particularly GVHD) and the limitations
imposed by finding human leukocyte antigen (HLA)matched
donors reduce the number of potential candidates
for this treatment. For this reason, the NCCN guidelines
reserve allo HCT for highly selected patients beyond second
relapse. 11 This section will discuss the literature available
that compares auto HCT with allo HCT, the use of MA or RI
conditioning, and options for treating relapse after allo HCT.
Auto HCT Compared with Allo HCT
There have been no sufficiently powered RCTs addressing
the relative benefits of auto compared with allo HCT for
indolent lymphoma. There have been several analyses comparing
outcomes of these two approaches, but they are
obviously limited by their nonrandomized and typically
retrospective design. For example, allo HCT is reserved for
later in the treatment course (often having relapsed after
auto HCT), so this generally selects for more advanced or
chemorefractory disease. Alternatively, because it is understood
that allo HCT is a higher-risk treatment, it may not be
offered to patients felt to be more frail. It is important to
appreciate such biases when assessing studies of this type,
but several potentially useful themes do emerge when reviewing
the results.
The largest auto HCT/MA allo HCT comparison included
904 patients with FL from the International Bone Marrow
Transplant Registry/Autologous Bone Marrow Transplant
Registry (IBMTR/ABMTR). 13 These were patients who received
transplantation during the 1990s, before the widespread
use of rituximab and RI allo HCT. The patients
receiving allo HCT were more likely to have worse performance
status, abnormal lactate dehydrogenase (LDH) levels,
advanced disease, and chemotherapy-resistant disease.
As mentioned above, the relative risk of TRM with allo HCT
was significantly higher compared with auto HCT (p �
0.001), while the relative risk of relapse was significantly
lower with allo HCT (p � 0.03). This yielded similar OS
between the groups, though there were more long-term
disease-free survivors with few late relapses in the allo HCT
cohort. Similar findings were reported in a smaller retrospective
analysis from investigators in the United Kingdom.
14 Interestingly, both studies suggested lower rates of
secondary malignancies in the allo HCT group potentially
because of the allogeneic graft replacing damaged host
hematopoiesis; though confounding factors—such as the use
total-body irradiation conditioning regimens—could have
contributed to these differences. 13,14
A prospective cohort study of auto HCT compared with
allo HCT in 216 patients with FL from the NCCN Outcomes
Database Project was recently presented in abstract form. 15
Importantly, these patients were all treated in the postrituximab
era. Additionally, the patients receiving allo HCT
received a mix of MA and RI conditioning, though the groups
were reported in aggregate. These investigators found that
allo HCT recipients were generally younger and more heavily
pretreated than those in the auto HCT cohort. With a
median follow-up of 2.9 years, they noted an overall nonrelapse
mortality (NRM) rate of 10% with auto HCT compared
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with 33% with allo HCT (p � 0.0001). The 3-year estimate of
failure-free survival (with “failure” defined as relapse, transformation,
disease progression, or death) was not different
between the two groups (p � 0.3), with a rate of 55% for auto
HCT compared with 56% for allo HCT. However, the 3-year
estimate of OS was significantly different (p � 0.001), with
a rate of 85% for auto HCT compared with 64% for allo HCT.
Using a multivariate analysis to adjust for age, number of
prior therapies, and disease status at the time of HCT, allo
HCT was still associated with an increased risk of death
(hazard ratio [HR] � 2.2, p � 0.01). Taken together, these
studies demonstrate the potential to control relapsed or
refractory disease with allo HCT, but the relative toxicities
compared with that of auto HCT make it a less attractive
option earlier in the disease course.
Lastly, the Bone Marrow Transplant Clinical Trials Network
performed a prospective study comparing auto HCT
with RI allo HCT in patients with relapsed but
chemotherapy-sensitive FL, but it closed early because of
slow accrual. 16 This study used a biologic treatment assignment,
where patients with an HLA-identical sibling received
RI allo HCT, and those without received auto HCT. Because
it closed early, statistical comparisons between the groups
could not be performed. Nevertheless, they did find that the
3-year OS and PFS for auto HCT was 73% and 63% (respectively;
20 patients), compared with 100% and 86% (respectively;
7 patients) for RI allo HCT. Although firm conclusions
cannot be drawn from this study, these data do suggest at
least comparable short-term efficacy between auto HCT and
RI allo HCT for chemotherapy-sensitive relapsed FL.
MA Allo HCT Compared with RI Allo HCT
Given the relative risks and benefits of allo HCT, it stands
to reason that this treatment approach would offer more
benefit if the toxicity could somehow be mitigated. With the
advent of RI conditioning regimens, this has become an
appealing modality for management of relapsed or refractory
indolent lymphoma. 2,3 Biologically, the growth kinetics
of this group of diseases would seem to make them amenable
to an approach in which the bulk of antimalignancy effects
are mediated by GVL. In particular, diseases that progress
more slowly may be less likely to outpace the engraftment
of the donor immune system, which is required to see GVL,
and less likely to require high-dose conditioning to induce
early disease control. Although limited prospective data
exist to support this rationale, again there are retrospective
analyses that can offer some evidence that this hypothesis is
correct.
The largest of these studies for indolent lymphoma comparing
RI with MA conditioning was a review of the IBMTR/
ABMTR registry. 17 They compiled 120 MA and 88 RI cases,
all of whom had FL. Patients in the RI cohort were noted to
be significantly older and later in the disease course, while
the MA cohort more frequently included patients with primary
refractory disease and bone marrow involvement.
Even though the type of conditioning did not correlate with
risk of TRM, PFS, or OS, recipients of RI allo HCT did have
a significantly higher risk of progression on multivariate
analysis (p � 0.044). These results are in contrast to a cohort
of 220 patients (84 of whom had indolent disease including
chronic lymphocytic leukemia [CLL] and T-cell lymphomas)
treated with either MA or RI allo HCT at Fred Hutchinson
Cancer Research Center (FHCRC). 18 Among patients with