2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

What Is the Role of Transplantation for
Indolent Lymphoma?
By Ryan D. Cassaday, MD, and Ajay K. Gopal, MD
Overview: Despite advances in chemoimmunotherapy, indolent
B-cell non-Hodgkin lymphomas (B-NHLs) are generally
not considered curable with this approach. Much attention has
been paid to the prospect of hematopoietic cell transplantation
(HCT) as a way to improve long-term outcomes for this
group of diseases. Autologous (auto) HCT provides intensive
conditioning therapy followed by rescue of hematopoiesis,
and this has been shown in randomized studies to prolong
survival compared with more standard chemotherapy, albeit
with increased short-term toxicity and the potential for higher
rates of secondary malignancies. Allogeneic (allo) HCT can
provide anticancer effects beyond the conditioning therapy
through the immune-mediated graft-versus-lymphoma (GVL)
B-NHLs are often classified into indolent and aggressive
subtypes. Indolent lymphomas typically include several
different specific histologies: follicular lymphoma (FL),
lymphoplasmacytic lymphoma (LPL), small lymphocytic
lymphoma (SLL), and marginal zone lymphoma (MZL). 1 The
vast majority of patients present with disseminated disease
requiring systemic therapy, which can improve overall survival
(OS) but is not thought to be curative. Over time,
indolent B-NHL becomes increasingly refractory to chemotherapy,
with shallower, shorter remissions the norm.
HCT is a strategy that aims to overcome the limitations of
standard chemoimmunotherapy in two general forms. Auto
HCT relies on the steep dose-response curve observed in
hematopoietic malignancies by using MA doses of chemoradiotherapy
followed by auto hematopoietic stem cell rescue.
In contrast, allo HCT also employs an immune-mediated
GVL effect to eradicate disease following preparative regimens
ranging in intensity from high-dose MA combinations
to very low-dose (2 Gy) radiation. The less intensive conditioning
strategies are designed to suppress the patient’s
immune system sufficiently to allow engraftment of the
donor hematopoietic cells and relies almost exclusively on
the GVL effect. 2,3 However, this same immunologic phenomenon
can affect normal healthy tissues in the patient,
inducing GVHD—the major source of morbidity and mortality
of this approach. 4 Nevertheless, allo HCT remains a
viable option for select patients as it can offer durable
remissions and the potential for cure in patients with
relapsed or refractory indolent lymphomas.
Indications for Auto HCT
Initial Consolidation
Auto HCT is generally not recommended as initial consolidation
of response for any indolent B-NHL outside the
context of a clinical trial. This conclusion is supported by at
least four prospective randomized controlled trials (RCTs)
that investigated this approach as part of first-line management
(Table 1). 5-8 Although most of these studies show
improved progression-free survival (PFS) or event-free survival
(EFS) when compared with standard chemotherapy,
overall survival (OS) has not been shown to be significantly
improved (p � 0.5 in the 3 studies where this comparison
was reported). Moreover, there appeared to be an increased
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effect. It can be administered following myeloablative (MA)
conditioning or reduced-intensity (RI) regimens aimed at sufficiently
suppressing the patient’s immune system to allow
engraftment of donor hematopoiesis. However, this same
potentially curative alloreactivity of the engrafted immune
system can lead to graft-versus-host disease (GVHD), a significant
cause of morbidity and mortality following allo HCT.
This article will discuss the current role of both auto HCT and
allo HCT in the management of indolent lymphoma as well as
the relative risks and benefits of each approach such that the
reader can place this in context of the multitude of options
available for patients with indolent B-NHL.
risk of secondary malignancies (both myeloid and solid
tumors) associated with auto HCT, which is becoming increasingly
relevant in indolent lymphoma as survival has
continued to improve with modern chemoimmunotherapy
regimens. Though select retrospective analyses have implicated
etoposide, alkylating agents, and total body irradiation
as increasing this risk, the study by Sebban and others
used these treatments as part of the transplant arm and saw
no increased incidence of secondary cancers compared to
the non-transplant arm. 8 In the trial that noted the highest
rates of secondary malignancies, Gyan and colleagues postulated
that the practice of in vitro purging of B lymphocytes
may have been responsible for this finding, perhaps by
affecting post-transplant immunosurveillance. 5 This process
is used rarely today with the application of in vivo B-cell
purging by rituximab.
Relapsed Disease
The major role of auto HCT remains its use in patients
with relapsed but chemotherapy-sensitive indolent B-NHL.
Unfortunately, most of the data supporting this approach
come from single-arm studies suggesting that a subset of
patients can again achieve long-term remissions with
this treatment. For example, in the previously mentioned
study by Ladetto et al, patients initially treated in the
chemotherapy-only arm were allowed to cross over to auto
HCT at the time of relapse. 6 Among the 28 patients salvaged
with this approach, the 3-year projected EFS and OS were
68% and 81%, respectively. Likewise, a retrospective study
from the United Kingdom in which patients received auto
HCT for FL in second or later remission showed a plateau in
the freedom from progression curve at 48% at 12 years
(median follow-up of 13.5 years), offering further evidence
that relapsed FL can be salvaged with auto HCT. 9 To date,
there has been a single small, but important, prospective
From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,
WA; Division of Medical Oncology, Department of Medicine, University of Washington,
Seattle, WA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Ajay Gopal, MD, 1100 Fairview Ave. N., Mailstop G3200,
Seattle, WA 98109; email: agopal@uw.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10