2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

for autologous SCT over conventional therapy. 19 Survival
was significantly longer for patients who had undergone
autologous SCT compared with patients conventionally
treated.
Results have now been reported for three phase III randomized
trials examining the role of autologous transplant
in CLL. 20-22 The European Intergroup Study randomly
selected 223 patients, 83% after first-line therapy and 17%
after second-line therapy. Only 59% of patients were in CR.
Patients were randomly selected to receive autologous SCT
(112 patients) and observation (111 patients). Autologous
SCT significantly improved EFS from 24.4 months in the
observation group to 51.2 months in the patients receiving
autologous SCT, but there was no difference in OS at 5
years. 20 In a second study, 241 patients received three
courses of cyclophosphamide, hydroxydaunorubicin, vincristine,
and prednisone/prednisolone (mini-CHOP), and then
three courses of fludarabine. Patients in CR were then
randomly selected to receive autologous SCT or observation,
whereas patients not in CR were randomly selected to
receive salvage therapy followed by either autologous SCT
or three courses of fludarabine plus cyclophosphamide (FC).
The patients achieving CR were also included for analysis in
the European Intergroup Study. Autologous SCT improved
EFS in patients achieving CR to initial therapy, but no
differences were observed among patients who required
salvage therapy. No difference in OS was found in either
group. 21 The GOELAMS LLC 98 trial compared six monthly
courses of cyclophosphamide, doxorubicin hydrochloride,
vincristine, and prednisone (CHOP) followed by six CHOP
courses every 3 months in responding patients with highdose
therapy with autologous SCT used as consolidation in
responding patients after three CHOP courses. A total of 86
patients were enrolled, with 43 patients evaluable after
autologous SCT. On an intent-to-treat basis and with a
median follow-up time of 77.1 months, median PFS was 22
months after conventional therapy and 53 months after
autologous SCT (p � 0.0001). There was no difference in OS
between the two arms. 25 Concerns regarding this trial
include the relatively small number of patients enrolled; the
trial had to be closed early because of concerns of emerging
better induction therapies, leading to a low statistical power.
The results obtained from these randomized studies all
demonstrate that patients with chemotherapy-sensitive disease
had prolongation in EFS but not OS. The question
KEY POINTS
● Autologous stem cell transplantation (SCT) is not
curative for chronic lymphocytic leukemia (CLL) and
should be performed only in the setting of clinical
trials.
● Myeloablative allogeneic SCT is applicable only to a
small population and is associated with unacceptably
high treatment-related morbidity and mortality.
● Reduced-intensity conditioning allogeneic SCT is potentially
curative but complicated by chronic GVHD.
● Identifying patients with CLL who should receive
transplantation and when in their clinical course this
should occur remains a major challenge.
400
Study
Table 1. Outcome after FCR or ASCT
Number of
Patients
remains if these patients would have had similar results if
they had been offered the type of chemoimmunotherapy that
is the standard of care today. Whereas great caution must be
taken comparing the outcome of separate studies, the outcomes
in terms of EFS and OS might be similar for patients
treated with fludarabine, cyclophosphamide, and rituximab
(FCR) and those receiving autologous SCT (Table 1). This
does not address whether improved outcome would be seen
with autologous SCT after FCR. In a phase II study, those
patients who received autologous SCT after front-line FCR
had an inferior outcome to patients who underwent autologous
SCT before chemoimmunotherapy was available. 15
Monoclonal antibodies have been used to increase the
likelihood of elimination of minimal residual disease (MRD)
after autologous SCT, ex vivo or by in vivo treatment with
alemtuzumab or rituximab. 15 Alemtuzumab was used in the
conditioning regimen for autologous SCT in one arm of the
German CLL Study Group CLL3 trial, and 12 of 16 patients
(87%) developed a skin rash between 43 and 601 days
post-SCT. In seven patients, biopsy confirmed GVHD that
persisted for a median duration of 517 (range, 60 to 867)
days. 23 The trial was discontinued because of the TRM, but
addition of alemtuzumab led to improved disease control.
When alemtuzumab was used at modified dose (10 mg
subcutaneously three times per week for 6 weeks) in 34
patients who had a clinical response to a fludarabine-based
regimen, the CR rate improved from 35% to 79.5% with 56%
achieving eradication of MRD. 24 Peripheral blood stem cell
collection was subsequently successfully performed in 92%.
Most studies reported relatively short follow-up and therefore
focus mostly on TRM early post-SCT, but late consequences—particularly
development of secondary
myelodysplasia and acute myeloid leukemia (MDS/AML)—
are of concern. Among 65 previously untreated patients who
were treated with fludarabine followed by autologous SCT,
eight developed MDS/AML, with a 5-year actuarial risk of
12% developing MDS/AML after autologous SCT. 16 Longterm
follow-up reports a high incidence of other solid tumors
in 31 (19%) patients. 15
Myeloablative Allogeneic SCT
Median
Age (y)
FCR
M. D. Anderson 8 300 57 51 at 5 y 77 at 6 y
CLL8 9 408 61 65 at 3 y 87 at 3 y
Autologous SCT
European Intergroup 20 112 54 42 at 5 y 86 at 5 y
SFGM-TC/GFLLC 21 52 in CR 56 79.8 at 3 y 96 at 3 y
46 not CR 48.9 at 3 y 82 at 3 y
GOELAMS 22 43 Upper age
limit 60
The major advantage of allogeneic SCT is the potential
for a GVL effect. There is strong evidence for a GVL effect in
CLL as demonstrated by a decreased risk of relapse in
patients with chronic GVHD, increased risk of relapse in
EFS
(%)
PFS 53 at
6.5 y
JOHN G. GRIBBEN
OS
(%)
107.4 at 6.5 y
Abbreviations: FCR, fludarabine, cyclophosphamide, and rituximab; ASCT,
autologous stem cell transplantation; y, years; EFS, event-free survival; OS,
overall survival; SFGM-TC, Societe’ Francaise de Greffe de Moelle et de Therapie
Cellulaire; GFLLC, Groupe Français d’étude de la Leucémie Lymphoïde Chronique;
CR, complete remission; GOELAMS, Groupe Ouest Est d’Etude des
Leucémies et Autres Maladies du Sang.