2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Transplant in Chronic Lymphocytic
Leukemia: To Do It or Not and If So, When
and How?
Overview: Most patients with chronic lymphocytic leukemia
(CLL) have an indolent clinical course, but the disease remains
incurable with standard therapy and the prognosis is dismal
for those patients with disease refractory to available treatment
options. The only potentially curative treatment is allogeneic
hematopoietic stem cell transplantation (SCT), but
since CLL is a disease of elderly patients, few patients are
candidates for myeloablative allogeneic SCT. Although autologous
SCT is feasible and has low treatment-related mortality,
it is not curative. The widespread adoption of reducedintensity
conditioning (RIC) allogeneic SCT has made this
approach applicable to the elderly patient population with
CLL. This approach relies on the documented graft-versus-
SCT IS NOT a suitable treatment option for the majority
of patients with CLL in whom the disease follows an
indolent course, and many patients never require therapy.
The outcome has improved dramatically over the past decade
for patients whose disease progresses to require treatment.
1 Most patients with CLL are elderly and not
sufficiently fit for SCT. However, it is possible to identify
suitable candidates for SCT using a number of clinical and
biologic features. 2 The role of SCT in a number of other
hematologic malignancies has been established in prospective
studies, but no studies in CLL have compared the
outcome after standard chemotherapy with allogeneic SCT.
The biggest challenges remain the decision of which patients
are eligible for SCT and when in their disease course SCT
should occur.
Patient Selection for SCT
CLL is an extremely heterogeneous disease, with the
clinical course varying from patients who never require
therapy to patients with rapidly progressive and fatal malignancy.
Treatment guidelines state that therapy should be
reserved for those with advanced, symptomatic, or progressive
disease. 3 For those patients whose disease requires
therapy, the results of randomized clinical trials have demonstrated
significant improvement over the past decade
with the use of combination chemotherapy and now chemoimmunotherapy.
4-9 When assessing the potential role of
transplantation, these approaches must be considered in
addition to the many exciting novel agents currently in
clinical trials, which may alter our approach as to when and
to whom transplant should be offered.
Major advances have been made in our understanding
of CLL pathophysiology, which has led to the emergence of
a large number of prognostic biomarkers cytogenetics, immunoglobulin
heavy chain (IgV H) gene mutational status,
zeta-associated protein 70 (ZAP70) expression, and CD38
expression. 10-13 The emergence of prognostic biomarkers
has implications for the selection for which patients might
merit SCT, but it is not yet fully clear how we should use
these factors in CLL management. 14
By John G. Gribben, MD, DSc
leukemia (GVL) effect and is strong in CLL. Steps to further
decrease the morbidity and mortality of the RIC SCT and in
particular to reduce the incidence of chronic extensive graftversus-host
disease (GVHD) remain a major focus. Many
potential treatments are available for CLL, and appropriate
patient selection and SCT timing remain controversial and the
focus of ongoing clinical trials. The use of SCT must always
be weighed against the risk of the underlying disease, particularly
in a setting where improvements in treatment are leading
to improved outcome. The major challenge remains how
to identify which patients with CLL merit this approach and
where in the treatment course this treatment can be applied
optimally.
Autologous SCT
The role of autologous SCT in CLL remains highly controversial
and there is currently no role for autologous SCT for
CLL except in the setting of a clinical trial. A number of
phase II studies have reported outcome following autologous
SCT for CLL, demonstrating that this approach is feasible
with a transplant-related mortality (TRM) of 1% to 10%,
with most toxicity occurring late. 15-17 Such studies need to
be considered in terms of intention to treat, and this can be
difficult to determine in transplant centers where only
responding might be referred. In a pilot study to assess the
feasibility of performing autologous SCT, 115 previously
untreated patients with CLL prospectively enrolled, and
only 65 (56%) proceeded to transplant. 16 TRM was low,
complete remission (CR) rate was 74%, the 5-year estimated
overall survival (OS) was 77.5%, and progression-free survival
(PFS) was 51.5%. Of concern, 8% of patients developed
post-transplant acute myeloid leukemia/myelodysplastic
syndrome, a complication also seen in other series. 15 In a
single-center study, among 137 patients who underwent
autologous transplantation, the one-year TRM was 4% but
rose to 10% when late events were taken into account. At the
median follow-up time of 6.5 years, OS was 58% after
autologous SCT. There was no TRM among 72 patients who
underwent autologous SCT in five Finnish centers. 17 Initial
enthusiasm for autologous SCT has been tempered since the
observed results demonstrated no plateau in either eventfree
survival (EFS) or OS and because of concerns regarding
the risk of secondary malignancies. 18
A retrospective matched-pair analysis was performed including
66 patients who had undergone a uniform high-dose
therapy and autologous SCT with a database of 291 patients
treated conventionally and suggested a survival advantage
From the Barts Cancer Institute, Queen Mary University of London, Charterhouse
Square, London.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests John G. Gribben, MD, DSc, Barts Cancer Institute, Queen Mary
University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; email:
j.gribben@qmul.ac.uk.
© 2012 by American Society of Clinical Oncology.
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