2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

WHEN TO OFFER TRANSPLANTATION IN CLL
Number of
Patients
Age
Years
(range)
patients who have undergone T-cell depletion, and clinical
responses to removal of immune suppression or to donor
lymphocyte infusion (DLI). 15 Allogeneic SCT has significant
morbidity and TRM, from regimen-related toxicity, GVHD,
and infection, but surviving patients have long-term disease
control. 15,25-27 In registry data, TRM following allogeneic
SCT in patients with CLL was unacceptably high at 46%,
with mortality from GVHD of 20%. 28 Currently there is only
a very limited role for myeloablative allogeneic SCT in the
setting of very young patients with particularly aggressive
disease. Among 25 patients with CLL who underwent allogeneic
SCT at the Fred Hutchinson Cancer Research Center
(FHCRC), grades 2 through 4 acute GVHD was seen in 14
patients, 10 developed clinically extensive chronic GVHD,
and estimated OS at 5 years was 32%. 29
No randomized studies have compared the outcome of
autologous SCT with allogeneic SCT. Studies from University
of Texas M. D. Anderson Cancer Center (MDACC)
demonstrate improved outcome after allogeneic SCT compared
with autologous SCT, suggesting that allogeneic SCT
can induce durable remission even in patients with refractory
disease. 30 At Dana-Farber Cancer Institute, 162 patients
with high-risk CLL were enrolled in a “biologic
randomization” in which 25 patients with a human leukocyte
antigen (HLA)-matched sibling donor underwent T
cell–depleted myeloablative allogeneic SCT, while 137 with
no HLA-matched sibling donor underwent B cell–purged
autologous SCT, with both groups receiving identical conditioning
regimen using high-dose cyclophosphamide and total
body irradiation. 15 The 100-day TRM was 4% after autologous
or allogeneic SCT, but later TRM had a major effect
on outcome. At the median follow-up of 6.5 years, PFS
was significantly longer following autologous than T cell–
depleted allogeneic SCT, but no significant differences were
observed in disease recurrence or deaths without recurrence
by type of transplant. There was no difference in OS between
the two groups, and at the median follow-up time of 6.5
years, OS was 58% after autologous and 55% after allogeneic
SCT.
RIC SCT for CLL
Prior
Regimens
(range)
Chemorefractory
(%)
Prior
Auto-SCT
A major advance in reducing the short-term morbidity and
mortality of allogeneic SCT has been the introduction of
Table 2. RIC Allogeneic SCT for CLL
Donor
(includes
mismatch) TRM
Acute
Grade 2–4
GVHD
Chronic
Extensive
Survival Reference
82 82 4 87% 4 63% related 25% overall 55% 49% related OS 50% 5 yr Sorror et al 2008 28
(42–72) 37% unrelated 53% unrelated PFS 45%
77 54 3 33% 10 81% related 18% 12 m 34% 58% OS 72% 2 yr Dreger et al 2003 29
(30–66) (0–8) PFS 56%
46 53 5 57% 10 33% related 17% overall 34% 43% OS 54% 2 yr Brown et al 2006 30
(35–67) (1–10) 67% unrelated PFS 34%
41 54 3 27% 11 58% related 5% at 100 d 10% 33%* OS 51 2 yr Delgado et al 2006 31
(37–67) (1–8) 42% unrelated 26% overall (grade 3–4) *after DLI PFS 45%
39 57 3 Not stated 90% related 2% at 100 d 45% 58% OS 48% 4 yr Khouri et al 2006 32
(34–70) (2–8) 10% unrelated PFS 44%
30 50 3 47% 50% related 13% overall 56% 21% OS 72% 2 yr Schetelig et al 2003 33
(12–63) (0–8) 50% unrelated PFS 67%
Abbreviations: RIC, reduced-intensity conditioning; SCT, stem cell transplantation; CLL, chronic lymphocytic leukemia; TRM, transplant-related mortality; GVHD,
graft-versus-host disease; OS, overall survival; PFS, progression-free survival; m, months; d, days.
nonmyeloablative or RIC regimens to allow engraftment of
allogeneic stem cells. This approach is much more applicable
to the age group with CLL who are potential candidates for
SCT. Most patients reported have been treated on experimental
treatment protocols with enrollment of many patients
with chemo-refractory end-stage disease.
RIC regimens allow transplantation in older patients,
making this approach more applicable to increased numbers
of patients with CLL and results from the larger reported
studies are shown in Table 2. 29-34 Most patients were
heavily pretreated and refractory to therapy, but despite
these issues, the majority demonstrated donor engraftment
and had a high CR rate. The ability of such approaches to
eradicate MRD in patients with advanced CLL and the
observation of late remissions in patients treated with low
doses of chemotherapy provide direct evidence for a powerful
GVL in CLL. 35 The outcome from the FHCRC multiinstitutional
protocol after RIC allogeneic SCT was reported
for 82 patients with advanced fludarabine-refractory CLL
using related (52 patients) or unrelated donors (30 patients)
median age 56 (range, 42 to 72). 29 TRM was 23% at 5 years,
with significant GVHD a remaining problem. Five-year OS
was 50% and EFS was 39%. Among 46 patients who underwent
RIC transplantation at Dana-Farber Cancer Institute—67%
using unrelated donors—factors associated with
increased risk of relapse include low levels of donor chimerism
at day 30, chemotherapy-refractory disease, increased
number of previous therapies, and adverse cytogenetics. 31
No formal assessment of RIC compared with myeloablative
allogeneic SCT has been undertaken, but the outcome
after RIC allogeneic SCT of 73 patients who had undergone
RIC was compared with that of 82 matched patients who
had undergone standard myeloablative conditioning for CLL
from the European Blood and Marrow Transplantation
(EBMT) registry database during the same time period.
Patients undergoing RIC transplants had significantly reduced
TRM but higher relapse incidence, and there was no
significant difference in OS or PFS between these two
groups. 36 Of particular interest is the report of 44 patients
with CLL with deletion of 17p and loss of p53 in whom
allogeneic SCT has the potential to induce long-term remission
in these very high-risk patients. 37
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