2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ROLE OF HCT FOR INDOLENT LYMPHOMA
Table 2. Summary of Results from Selected Prospective Trials of Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation
for Indolent Lymphoma
Study
(Sample Size)
Morris et al23 2004
(n � 41 low-grade^ ; 88 total)*
Rezvani et al22 2008
(n � 62; 16 with HT)
Khouri et al21 2008
(n � 47, all FL)
Piñana et al24 2010
(n � 37, all FL)
Thomson et al26 2010
(n � 82, all FL)*
Shea et al25 2011
(n � 16 FL; 47 total)
Conditioning
Regimen
GVHD
Prophylaxis
indolent histologies, there was a significantly higher NRM
(p � 0.02), a trend toward higher overall mortality (p �
0.07), and a nonsignificantly lower risk of relapse after MA
(p � 0.33) compared with RI allo HCT. These authors also
used the Hematopoietic Cell Transplant-Comorbidity Index
(HCT-CI) to estimate risk based on pretransplant comorbidities,
but this analysis was performed for the entire study
cohort, irrespective of histology. 19 In patients with a lowrisk
HCT-CI score, there was no difference in NRM, relapse
rate, or OS at 3 years between patients receiving RI or MA
allo HCT. However, in patients with an intermediate- or
high-risk HCT-CI score, the RI patients had significantly
lower NRM (p � 0.001) and significantly higher OS (p �
0.007) compared with MA patients, but relapse rates were
not statistically different (p � 0.26). Another relatively large
registry study from the European Group for Blood and
Marrow Transplantation came to comparable conclusions,
though this study was unique in that it restricted the
analysis to patients with HLA-matched unrelated donors. 20
In 131 patients with FL, MA allo HCT was associated with
significantly worse outcomes for NRM, PFS, and OS by
multivariate analysis (p � 0.01 for all three endpoints).
Although the data are not conclusive, it would appear that
RI allo HCT may offer long-term disease control with less
risk of serious toxicity compared with MA allo, perhaps most
relevant in patients with significant comorbidities.
Focus on RI Allo HCT
There have been several prospective studies focusing on
the outcome of indolent lymphomas following RI allo HCT,
but all have been single-arm trials (Table 2). 21-26 One
important finding seen in each of these studies is that
relapses of indolent lymphoma following RI allo HCT were
rarely seen past 3 years. The study by Khouri et al was
recently updated and presented in abstract form. They have
seen only one additional recurrence of FL with an added
3 years of follow-up, yielding 10-year estimates of OS of
78% and PFS of 72%. 27 In the study by Thomson et al, the
Prior Tx: Median
(Range)
Prior
Auto HCT aGVHD, cGVHD NRM/TRM EFS/PFS OS
Flu/Mel Alem � CSP 3 (1–6)# 37% 15%, 5%# 11% 65% 73% 3 yrs
TBI (18%),
Flu/TBI (82%)#
CSP � MMF 6 (1–19)# 44%# 63%, 47%# 42%# 43% 52% 3 yrs
FCR TAC � MTX 3 (2–7) 19% 11%
36%
15% 83% 85% 5 yrs
Flu/Mel CSP � MTX 3 (NR) 46% 51%, 53% 37% 55% 57% 4.3 yrs
Flu/Mel Alem � CSP 4 (1–8) 26% 13%, 18% 15% 76% 76% 3.6 yrs
FC TAC 2 (1–3) 0% 29%, 18%# 14%# 75% 81% 4.6 yrs
Abbreviations: GVHD, graft-versus-host disease (a � acute �Grades 2–4�, c � chronic �extensive�); Tx, treatment; auto HCT, autologous hematopoietic cell
transplantation; aGVHD, acute GVHD (grades 2–4); cGVHD, chronic GVHD (extensive); NRM, nonrelapse mortality; TRM, treatment-related mortality; EFS, event-free
survival; PFS, progression-free survival; OS, overall survival; F/U, follow-up; Flu, fludarabine; Mel, melphalan; Alem, alemtuzumab; CSP, cyclosporine; yrs, years; HT,
histologic transformation; TBI, total body irradiation; MMF, mycophenolate mofetil; FL, follicular lymphoma; FCR, fludarabine, cyclophosphamide, and rituximab; TAC,
tacrolimus; MTX, methotrexate; NR, not reported; FC, fludarabine and cyclophosphamide.
^
Specific histologies comprised within this group are as follows: 29 follicular lymphomas, three lymphoplasmacytic lymphomas, and 9 chronic lymphocytic or
prolymphocytic leukemias.
* Nineteen of the patients treated in the study by Thomson et al from 2010 were also described in the report by Morris et al from 2004 but with more than 5 years
of additional follow-up. Since this comprised a minority of the patients in the Morris study, it was included as its own reference.
# The data reported were not segregated by histology and therefore represent the result for the entire study cohort, not exclusively for patients with low-grade
lymphoma
Median
F/U
latest relapse seen was at 43 months, with no other relapses
seen past 3 years. 26 A few other salient features from these
studies are worth mentioning.
First, patients included in these studies were generally
heavily pretreated, with a substantial portion in some of the
studies having received prior auto HCT. This is in keeping
with the NCCN guidelines that allo HCT should generally
be reserved for patients with relapsed for refractory disease.
11 There were varying degrees of chemotherapy sensitivity
across the trials. The studies by Khouri et al and Shea
et al exclusively enrolled patients who were in either complete
remission (CR) or partial remission (PR), which may in
part explain why these studies had some of the best survival
outcomes. 21,25 The report by Piñana et al noted a nonsignificant
trend in 4-year OS according to disease status (71% for
those in CR, 48% for those in PR, and 29% for refractory or
progressive disease [PD]; p � 0.09). 24 In the largest of these
studies, Thomson et al noted that the absence of prior auto
HCT predicted for improved OS and PFS in a univariate
analysis, but this did not persist following multivariate
analysis. 26 The studies by Morris et al and Rezvani et al
supported the concept that chemotherapy sensitivity and
disease status at the time of transplantation are predictive
of outcome. 22,23 However, even in these seemingly higherrisk
patients, salvage and long-term remission is possible
with this approach.
Another issue in these studies worth addressing is the
effect of GVHD on outcome. Classically, GVHD is an indication
of an immunologically active allograft, which should
also be capable of mediating GVL effects. However, GVHD
remains the major cause of morbidity and NRM in allo HCT.
Although none of these studies were designed to determine
the best method of GVHD prophylaxis, two of these studies
from the same group used a strategy of partial in vivo T-cell
depletion using the anti-CD52 antibody alemtuzumab. 23,26
In these studies, the authors noted a relatively low incidence
of GVHD. However, relapse rates with this approach were
higher than that seen in the other prospective studies
497