Biol Blood Marrow Transplant 20 (2014) 1813e1818
Biology of Blood and
Marrow Transplantation
journal homepage: www.bbmt.org
Favorable Outcomes from Allogeneic and Autologous Stem Cell
Transplantation for Patients with Transformed Nonfollicular
Indolent Lymphoma
Diego Villa 1, 2, *, Anupkumar George 3, John F. Seymour 3, Cynthia L. Toze 4, Michael Crump 1,
Christina Lee 5, Rena Buckstein 5, Douglas A. Stewart 6, David MacDonald 7, Ronan Foley 8,
Anargyros Xenocostas 9, Mitchell Sabloff 10, Neil Chua 11, Felix Couture 12, Jean F. Larouche 13,
Sandra Cohen 14, Kerry J. Savage 2, Joseph M. Connors 2, Tony Panzarella 15, Dennis A. Carney 3,
Michael Dickinson 3, John Kuruvilla 1
1
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
4
Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada
5
Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
6
Tom Baker Cancer Centre, Calgary, Alberta, Canada
7
Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada
8
Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
9
London Health Sciences Centre, London, Ontario, Canada
10
The Ottawa Hospital, Ottawa, Ontario, Canada
11
Cross Cancer Institute, Edmonton, Alberta, Canada
12
Hotel Dieu de Quebec, Quebec City, Quebec, Canada
13
Hôpital de l’enfant Jesus, Quebec City, Quebec, Canada
14
Maisonneuve Rosemont Hôpital, Montreal, Quebec, Canada
15
Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
2
3
Article history:
Received 18 April 2014
Accepted 8 July 2014
Key Words:
Rituximab
Transformed lymphoma
Autologous transplant
Allogeneic transplant
a b s t r a c t
The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with
transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort
study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or
subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a
cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n ¼ 47) or auto-SCT
(n ¼ 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%)
small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or
platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%)
subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after
transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT
40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related
mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients
with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P ¼ .38, P ¼ .69, and P ¼ .54, respectively).
Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent
lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.
Ó 2014 American Society for Blood and Marrow Transplantation.
Financial disclosure: See Acknowledgments on page 1817.
* Correspondence and reprint requests: Diego Villa, MD, MPH, British
Columbia Cancer Agency, 600 West 10th Avenue, Division of Medical
Oncology, Vancouver, BC V5Z 4E6, Canada.
E-mail address: [email protected] (D. Villa).
http://dx.doi.org/10.1016/j.bbmt.2014.07.015
1083-8791/Ó 2014 American Society for Blood and Marrow Transplantation.
INTRODUCTION
Patients with indolent non-Hodgkin lymphomas may
experience disease transformation to aggressive histology
1814
D. Villa et al. / Biol Blood Marrow Transplant 20 (2014) 1813e1818
lymphoma during the course of their disease. This risk is
approximately 2% to 3% per year in patients with follicular
lymphoma (FL) [1-4]. The incidence and clinical course of
patients with other nonfollicular indolent histologies experiencing transformation appear to be similar based on
limited data [5-8].
Several studies suggest that certain patients with transformed indolent lymphomas may benefit from allogeneic
(allo-) or autologous stem cell transplantation (auto-SCT).
However, these studies have included only patients with
transformed FL [9-16] or a minority of patients with other
indolent histologies [17-25]. No large studies have evaluated
SCT strategies exclusively in patients with transformed nonFL, with the exception of Richter’s transformation in chronic
lymphocytic leukemia [26-28]. Therefore, the purpose of this
study was to evaluate outcomes after allo-SCT or auto-SCT in
patients with transformed non-FL and to compare them with
a similar population of patients with transformed FL undergoing the same treatments.
METHODS
Patient Identification
This is an international, multicenter cohort study of patients with
transformed non-FL who were treated with allo-SCT or auto-SCT during
1996 to 2013. Canada has no centralized transplant data repository, and
therefore all transplant centers in the Canadian Blood and Marrow Transplant Group were contacted. These transplant centers reported all cases
with transformed indolent lymphoma treated with SCT, which were combined into a database of 391 patients. Results for the subgroup of patients
with transformed FL were previously published [14] but not for those with
transformed nonfollicular indolent histologies. In Australia, there is a
voluntary but complete registration and reporting process to a national stem
cell transplantation registry. However, for this study, data for all eligible
similar transplant cases treated only at Peter MacCallum Cancer Centre,
Melbourne, Australia, were collected from the institutional database.
Adult patients with biopsy-proven indolent non-Hodgkin lymphoma
and subsequent biopsy-proven aggressive histology B cell lymphoma
transformation treated with allo-SCT or auto-SCT were included. Patients
who initially presented with simultaneous indolent and aggressive histologies (discordant or composite) were excluded. Patients transplanted for a
subsequent diagnosis of Hodgkin lymphoma or T cell lymphoma and those
with a clinical diagnosis of transformation without biopsy confirmation
were excluded. Patients with an initial diagnosis of aggressive lymphoma
with a subsequent indolent histology relapse were also excluded. Pathology
was reviewed at each academic center for transformed lymphoma cases
before SCT.
Disease and Treatment Data
Standard staging investigations, including computed tomography scans
and bone marrow biopsies, were completed at the time of diagnosis and
transformation. 18-F deoxyglucose positron emission tomography scans
were not routinely performed. Advanced stage at transformation was
defined as Ann Arbor stage III or IV or stage I or II with B symptoms or bulky
disease (10 cm).
At the time of transformation, patients received at least 1 cycle of
combination chemotherapy, most commonly anthracycline or platinumcontaining, with or without rituximab. Response to chemotherapy was
retrospectively interpreted by participating physicians according to the
1999 International Working Group criteria [29]. Patients underwent alloSCT or auto-SCT for any episode of transformation (first or subsequent
relapse) and were selected for SCT primarily on the basis of chemosensitivity. Similar criteria were applied for response evaluation after alloSCT or auto-SCT. The choice of chemotherapy regimens, SCT type, stem
cell source and mobilization procedures, graft-versus-host disease prophylaxis, and supportive care followed individual institutional standards.
Statistical Analysis
Overall survival (OS), calculated from the date of allo-SCT or auto-SCT to
the date of last follow-up or death from any cause, was the primary
endpoint. Progression-free survival (PFS), calculated from the date of alloSCT or auto-SCT to the date of last follow-up (censored observations) or
subsequent progression, relapse, or death from any cause (events), was a
secondary endpoint. Nonrelapse mortality (NRM) was calculated from the
date of allo-SCT or auto-SCT to the date of last follow-up (censored
Table 1
Patient Characteristics at Time of Diagnosis of Indolent Lymphoma and
Transformation
Characteristics
Allo-SCT
(n ¼ 12)
Auto-SCT
(n ¼ 22)
n
n
%
P
%
At diagnosis of indolent lymphoma
Country
Canada
Australia
Male gender
Age at diagnosis, yr
Median
Range
Indolent histology at original
diagnosis
Marginal zone lymphoma
Chronic lymphocytic leukemia
Lymphoplasmacytic lymphoma
Small lymphocytic lymphoma
Systemic regimens for iNHL
0
1
2-3
Pretransformation radiotherapy
10
2
4
84
17
33
48
24-64
15
7
10
68
32
46
53
32-64
.30
.72
.29
.05
3
6
2
1
25
50
17
8
12
5
0
5
55
23
0
23
3
6
3
1
25
50
25
8
4
12
6
5
18
55
27
23
7
5
58
42
12
10
55
45
.90
.39
At diagnosis of transformation
Year of transformation
1996-2005
2006-2013
Years from iNHL to transformation
Median
Range
Transformation histology
Diffuse large B cell lymphoma
Burkitt-like lymphoma
Advanced stage
Elevated LDH*
Systemic regimens for
transformation
1
2
3
Last line of chemotherapy
CHOP
Platinum-containing
Othery
Last chemotherapy with rituximab
1.0
.12
2.1
.6-7.7
2.9
.4-18.3
.35
11
1
12
3/7
92
8
100
43
22
0
19
12/19
100
0
86
63
8
3
1
67
25
8
14
7
1
64
32
4
7
3
2
7
58
25
17
58
5
14
3
18
27
64
14
82
.54
.41
.85
.08
.22
iNHL indicates indolent non-Hodgkin lymphoma; LDH, lactate dehydrogenase; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone.
* Number of patients/number of patients with available data.
y
Other regimens such as carmustine, etoposide, cytarabine, melphalan
(mini-BEAM) and cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, methotrexate (hyper-CVAD).
observations) or death from any cause before lymphoma relapse or progression (events). Death within 100 days of transplant was considered as
transplant-related mortality.
Outcomes were also compared with a cohort of 246 patients with
transformed FL treated with either allo-SCT (n ¼ 47) or auto-SCT (n ¼ 199)
across the same institutions, countries, and time period, identified within
the databases described above. Patient characteristics at diagnosis, transformation, and transplantation were compared between groups using
Fisher’s exact test for discrete variables and Student’s t-test for continuous
variables. Three-year OS, PFS, and NRM rates were estimated using the
Kaplan-Meier method and compared using the log-rank test [30]. Data were
analyzed using SPSS version 14.0 for Windows (SPSS Inc., Chicago, IL).
RESULTS
Patient Characteristics
Patient and treatment characteristics are described in
Tables 1 and 2. Thirty-four patients (25 Canada, 9 Australia)
were identified with the following underlying indolent
histologies: 15 (44%) marginal zone lymphoma, 11 (32%)
chronic lymphocytic leukemia, 6 (18%) small lymphocytic
D. Villa et al. / Biol Blood Marrow Transplant 20 (2014) 1813e1818
Table 2
Patient Characteristics at Time of Stem Cell Transplantation
Characteristics
Year of transplantation
1996-2005
2006-2013
Age at SCT, yr
Median
Range
Months from transformation to SCT
Median
Range
Chemosensitivity pre-SCT
Complete response
Partial response
Stable disease
Progressive disease
Stem cell source
Peripheral blood
Bone marrow
High-dose (conditioning) regimen
Chemotherapy þ total body
irradiation
Chemotherapy only
Allogeneic donor type
Matched sibling
Mismatched related donor
Matched unrelated donor
Graft-versus-host disease
Acute
Chronic
Prophylaxis
Cyclosporine þ methotrexate
Cyclosporine þ mycophenolate
Antithymocyte infusion
Response to SCT
Complete response
Partial response
Stable disease
Progressive disease
Not assessed*
Transplant-related mortality
at 100 d
Allo-SCT
(n ¼ 12)
Auto-SCT
(n ¼ 22)
n
%
n
%
58
42
8
14
36
64
P
.29
7
5
.11
55
26-67
58
43-66
6
2-19
6
2-86
.13
.04
1
9
1
1
8
77
8
8
11
11
0
0
50
50
0
0
4
8
33
67
22 100
0
0
6
50
6
50
3
4
5
25
33
42
<.001
<.001
1
4
21 96
Not applicable
Not applicable
5
5/11*
42
45
11
1
4
92
8
33
6
3
0
1
2
2
50
25
0
8
17
17
19
3
0
0
0
0
86
14
0
0
0
0
.06
.12
Two allo-SCT patients experienced transplant-related mortality before
response assessment.
*
lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patient and disease characteristics were generally similar between both transplant groups, both at the time of diagnosis
of indolent and at the time of transformation.
Most transformation events occurred in patients who had
received 1 to 2 lines of systemic therapy for their indolent
lymphoma. The median time from initial diagnosis of indolent
lymphoma to transformation was 2.5 years, with a wide time
range (.4 to 18 years). At transformation, approximately half of
the patients had an elevated serum level of lactate dehydrogenase and almost all had advanced stage disease. Patients
received various anthracycline or platinum-containing
chemotherapy regimens for transformation, incorporating
rituximab in 25 patients (74%), with no significant difference
in frequency between allo-SCT and auto-SCT (P ¼ .22).
Transplantation Characteristics
Twelve patients (35%) were treated with allo-SCT and 22
(65%) with auto-SCT. None of the patients in the allo-SCT
group underwent prior auto-SCT for relapsed indolent lymphoma. Twenty-two (65%) received SCT as part of their
upfront therapy (immediately after 1 line of chemotherapy
for transformed disease), whereas the other 12 (35%)
1815
received it in the relapsed setting (after 2 to 3 lines of
chemotherapy for transformed disease).
Most patients were transplanted with chemosensitive
disease (83% allo-SCT, 100% auto-SCT). Compared with alloSCT patients, those treated with auto-SCT were more likely
to be transplanted in a slightly more recent era and at an
older age, using peripheral blood stem cells, and after a highdose therapy regimen that did not include total body
irradiation. All patients undergoing allo-SCT received myeloablative conditioning. For the 12 allo-SCT patients, donors
were 3 matched siblings, 5 matched unrelated, and 4 mismatched related. Transplant-related mortality at 100 days
was 17% and 0% for allo-SCT and auto-SCT, respectively
(P ¼ .12).
Outcomes
With a median follow-up of 3.7 years (range, .4 to
10.7 years) in surviving patients, the 3-year OS rate after SCT
for the entire cohort was 67% (standard error [SE], 9%), with
no statistical difference between patients treated with alloSCT (54%; SE, 15%) or auto-SCT (74%; SE, 10%), P ¼ .16, as
shown in Figure 1. The 3-year PFS rate after SCT for the entire
cohort was 49% (SE, 9%), again with no statistical difference
between patients treated with allo-SCT (40%; SE, 15%) or
auto-SCT (54%; SE, 11%), P ¼ .13, as shown in Figure 2. The 3year NRM rate after SCT for the entire cohort was 14% (SE,
7%), which was significantly greater in patients treated with
allo-SCT (15%; SE, 15%) compared with auto-SCT (7%; SE, 6%;
P ¼ .02; Figure 3).
Outcomes were then compared with a cohort of 246 patients with transformed FL treated with allo-SCT (n ¼ 47) or
auto-SCT (n ¼ 199). Patient, disease, and treatment characteristics were similar between patients with transformed FL
and non-FL, with the exception of a significantly higher
proportion of males in the former group (Supplemental
Tables 1 and 2). Adjusted for type of SCT only, the 3-year
OS rate after allo-SCT was statistically similar for patients
with non-FL (47%; SE, 8%) and FL (54%; SE, 15%). Correspondingly, the 3-year OS rate for non-FL transformed lymphoma after auto-SCT (74%; SE, 10%) was statistically similar
to that of patients with transformed FL (68%; SE, 3%), with
P ¼ .38 for all adjusted comparisons, as shown in
Supplemental Figure 1.
Adjusted for type of SCT only, the 3-year PFS rate after
allo-SCT (40%; SE, 15%) was statistically similar to that of
patients with transformed FL (46%; SE, 8%). Correspondingly,
the 3-year PFS rate after auto-SCT (54%; SE, 11%) was statistically similar to that of patients with transformed FL (49%;
SE, 4%), with P ¼ .69 for all adjusted comparisons, as shown in
Supplemental Figure 2. Adjusted for type of SCT only, the 3year NRM rate after allo-SCT (17%; SE, 11%) was statistically
similar to that of patients with transformed FL (36%; SE, 8%).
Correspondingly, the 3-year NRM rate after auto-SCT (7%;
6%) was statistically similar to that of patients with transformed FL (6%; SE,2%), with P ¼ .54 for all adjusted comparisons, as shown in Supplemental Figure 3.
DISCUSSION
This report presents our multi-institutional, retrospective
analysis of the outcomes of transformed non-FL patients
treated with allo-SCT or auto-SCT. We observed that patients
with transformed non-FL treated with hematopoietic SCT
experience outcomes comparable with those of patients with
transformed FL receiving similar treatments. This suggests
the biology of the aggressive component, rather than that of
D. Villa et al. / Biol Blood Marrow Transplant 20 (2014) 1813e1818
1.0
1.0
0.8
0.8
0.6
Nonrelapse Mortality
Overall Survival
1816
AUTO 3-yr OS 74%
ALLO 3-yr OS 54%
0.4
P = .16
0.2
P = .02
0.6
ALLO 3-yr NRM 15%
0.4
0.2
AUTO 3-yr NRM 7%
0.0
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
0
1
2
3
4
5
6
7
8
9
10
11
12
Time since transplantation (years)
Time since transplantation (years)
Figure 1. Overall survival by transplant type (n ¼ 34). AUTO indicates autoSCT (green); ALLO, allo-SCT (blue).
Figure 3. Nonrelapse mortality by transplant type (n ¼ 34). AUTO indicates
auto-SCT (green); ALLO, allo-SCT (blue).
the indolent lymphoma, drives prognosis in these patients.
Our data therefore corroborate that allo-SCT and auto-SCT
may be appropriate treatments for patients with transformed indolent lymphoma regardless of the underlying
histology.
Overall, our OS and PFS estimates are consistent with
other cohorts of various transformed indolent histologies in
the literature. Ban-Hoefen et al. [18] published a retrospective analysis of the National Comprehensive Cancer Network
database of 118 patients with transformed indolent lymphoma (14% non-FL), in which the 2-year OS rate was 65% for
patients undergoing allo-SCT (n ¼ 18) and 83% for those
receiving auto-SCT (n ¼ 50). Villa et al. [25] described a
single-institution cohort of 105 patients (4% non-FL) with
transformed indolent lymphoma in which the 3-year OS and
PFS rates were 54% and 42%, respectively, for the subgroup of
50 patients who proceeded with auto-SCT. In this cohort,
only 4 patients received allo-SCT [25]. Finally, in a subgroup
analysis of the National Cancer Institute of Canada LY-12
randomized trial of salvage chemotherapy and auto-SCT for
relapsed/refractory aggressive non-Hodgkin lymphomas, the
subset of 89 patients with transformed indolent lymphomas
experienced 4-year event-free survival rate after auto-SCT of
45% [21].
Studies of SCT for transformed indolent lymphomas have
not compared outcomes according to FL versus non-FL histology, with the exception of a retrospective study of 27
patients with transformed indolent lymphoma that found no
differences in disease-free survival or OS between patients
with transformed chronic lymphocytic leukemia/small
lymphocytic lymphoma (n ¼ 6) or FL (n ¼ 21) treated with
auto-SCT (P ¼ .66) [20]. A few publications of auto-SCT and
allo-SCT for Richter’s transformation of chronic lymphocytic
leukemia/small lymphocytic lymphoma suggest that a subgroup of patients may benefit from such treatments [26-28].
However, our chronic lymphocytic leukemia/small lymphocytic lymphoma subgroup was not large enough to determine whether these patients benefit from allo-SCT over
auto-SCT compared with other indolent histologies.
The main strength of the present analysis is that the study
base was assembled through a multi-institutional collaboration, reflecting a broad pattern of practice. Additionally, results
were compared with a very large cohort of 246 patients with
transformed FL treated with allo-SCT or auto-SCT, in actuality
much larger than any other published in the literature.
Because FL is more common than the other individual B cell
lymphoid cancer subtypes, studies of transformed indolent
lymphoma have included none [9-16] to few [17-25] patients
with non-FL. Although the present study represents a
considerable experience of SCT in patients with transformed
non-FL, data collected on 34 patients transplanted over
17 years may not necessarily reflect the current state of
transplant outcome in similar patient populations.
Our study has several limitations. First, the patients reported in our series were highly selected for allo-SCT or autoSCT based on multiple factors, including age, fitness,
response to chemotherapy, and physician and patient choice.
Therefore, results may not be necessarily generalized to the
greater population of patients with transformed non-FL
potentially eligible for SCT. Second, given the retrospective,
nonrandomized design, comparisons between groups are
1.0
Progression-Free Survival
0.8
0.6
AUTO 3-yr PFS 54%
0.4
ALLO 3-yr PFS 40%
P = .13
0.2
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time since transplantation (years)
Figure 2. Progression-free survival by transplant type (n ¼ 34). AUTO indicates auto-SCT (green); ALLO, allo-SCT (blue).
D. Villa et al. / Biol Blood Marrow Transplant 20 (2014) 1813e1818
imbalanced. Because of the small sample size, our analysis
lacks sufficient statistical power to identify modest differences. Third, various indolent lymphomas, each with a
particular natural history and specific management, were
combined for analysis. Ideally, the management and outcomes of each indolent subtype transformation should be
evaluated separately, but our small sample size did not
permit such analysis. Fourth, 18-F deoxyglucose positron
emission tomography was not routinely performed in patients included in this study. The lack of these data makes it
difficult to determine how well balanced the allo-SCT and
auto-SCT groups were, especially in the view of the difference in chemosensitivity between both groups shown in
Table 2.
Additionally, all allo-SCT patients underwent myeloablative conditioning, which likely contributed to the high
transplant-related mortality in this group. A recent report
from the Center for International Blood and Marrow Transplant Research suggests that reduced-intensity conditioning
allo-SCT may maintain efficacy while reducing toxicity in
patients with transformed FL [16]. Furthermore, the allo-SCT
group is heterogeneous, including recipients of stem cells
from matched related, matched unrelated, and mismatched
related donors. Given the study time period, current standards for HLA matching were not routinely performed for
most cases, limiting the ability to understand the outcomes
of allo-SCT in this series.
Finally, about 80% of the patients in our study received
rituximab-containing salvage chemotherapy before SCT.
Unfortunately data on prior rituximab use for indolent
lymphoma (before transformation) were not available.
Again, the sample size limited our ability to draw any conclusions about the impact of rituximab. Limited retrospective
data suggest that the addition of rituximab to chemotherapy
improves outcomes in patients with transformed indolent
lymphoma who proceed with auto-SCT, although the effect
in patients treated with allo-SCT is largely unknown
[18,25,31-33].
In summary, auto-SCT and allo-SCT may be reasonable
treatments for selected patients with transformed indolent
non-FL, although outcomes and toxicity appear to be more
favorable with auto-SCT. In the short to medium term (up to
5 years after allo-SCT or auto-SCT), there is no clear advantage to any particular transplantation strategy, although
longer observation is required to clarify whether there truly
is a fraction of patients cured with either modality. Further
research is necessary to determine the optimal strategy,
including timing, drug sequencing, and combinations with
the most favorable benefit-to-risk ratio.
ACKNOWLEDGMENTS
The authors acknowledge all contributors to this study.
Portions of the article were presented previously at the
12th International Conference on Malignant Lymphoma,
June 19 to 22, 2013, Lugano, Switzerland.
Financial disclosure: Supported by a 2010 Canadian Blood
and Marrow Transplant Group Small Budget Research Grant.
Conflict of interest statement: There are no conflicts of
interest to report.
SUPPLEMENTARY DATA
Supplementary data related to this article can be found
online at http://dx.doi.org/10.1016/j.bbmt.2014.07.015.
1817
REFERENCES
1. Al-Tourah AJ, Gill KK, Chhanabhai M, et al. Population-based analysis of
incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin
Oncol. 2008;26:5165-5169.
2. Bastion Y, Sebban C, Berger F, et al. Incidence, predictive factors, and
outcome of lymphoma transformation in follicular lymphoma patients.
J Clin Oncol. 1997;15:1587-1594.
3. Conconi A, Ponzio C, Lobetti-Bodoni C, et al. Incidence, risk factors and
outcome of histological transformation in follicular lymphoma. Br J
Haematol. 2012;157:188-196.
4. Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of
transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007;25:2426-2433.
5. Dungarwalla M, Appiah-Cubi S, Kulkarni S, et al. High-grade transformation in splenic marginal zone lymphoma with circulating villous
lymphocytes: the site of transformation influences response to therapy
and prognosis. Br J Haematol. 2008;143:71-74.
6. Robertson LE, Pugh W, O’Brien S, et al. Richter’s syndrome: a report on
39 patients. J Clin Oncol. 1993;11:1985-1989.
7. Sretenovic M, Colovic M, Jankovic G, et al. More than a third of nongastric malt lymphomas are disseminated at diagnosis: a single center survey. Eur J Haematol. 2009;82:373-380.
8. Zucca E, Conconi A, Pedrinis E, et al. Nongastric marginal zone B-cell
lymphoma of mucosa-associated lymphoid tissue. Blood. 2003;101:
2489-2495.
9. Andreadis C, Schuster SJ, Chong EA, et al. Long-term event-free survivors after high-dose therapy and autologous stem-cell transplantation
for low-grade follicular lymphoma. Bone Marrow Transplant. 2005;36:
955-961.
10. Chen CI, Crump M, Tsang R, et al. Autotransplants for histologically
transformed follicular non-Hodgkin’s lymphoma. Br J Haematol. 2001;
113:202-208.
11. Foran JM, Apostolidis J, Papamichael D, et al. High-dose therapy with
autologous haematopoietic support in patients with transformed
follicular lymphoma: a study of 27 patients from a single centre. Ann
Oncol. 1998;9:865-869.
12. Sabloff M, Atkins HL, Bence-Bruckler I, et al. A 15-year analysis of early
and late autologous hematopoietic stem cell transplant in relapsed,
aggressive, transformed, and nontransformed follicular lymphoma. Biol
Blood Marrow Transplant. 2007;13:956-964.
13. Thomson KJ, Morris EC, Bloor A, et al. Favorable long-term survival
after reduced-intensity allogeneic transplantation for multiple-relapse
aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27:426-432.
14. Villa D, Crump M, Panzarella T, et al. Autologous and allogeneic stemcell transplantation for transformed follicular lymphoma: a report of
the Canadian blood and marrow transplant group. J Clin Oncol. 2013;
31:1164-1171.
15. Williams CD, Harrison CN, Lister TA, et al. High-dose therapy and
autologous stem-cell support for chemosensitive transformed lowgrade follicular non-Hodgkin’s lymphoma: a case-matched study
from the European Bone Marrow Transplant Registry. J Clin Oncol.
2001;19:727-735.
16. Wirk B, Fenske TS, Hamadani M, et al. Outcomes of hematopoietic
cell transplantation for diffuse large B cell lymphoma transformed
from follicular lymphoma. Biol Blood Marrow Transplant. 2014;20:
951-959.
17. Ban-Hoefen M, Kelly JL, Bernstein SH, et al. High-dose therapy and
autologous stem cell transplant for transformed non-Hodgkin lymphoma in the rituximab era. Leuk Lymph. 2012;53:830-835.
18. Ban-Hoefen M, Vanderplas A, Crosby-Thompson AL, et al. Transformed
non-Hodgkin lymphoma in the rituximab era: analysis of the NCCN
outcomes database. Br J Haematol. 2013;163:487-495.
19. Eide MB, Lauritzsen GF, Kvalheim G, et al. High dose chemotherapy
with autologous stem cell support for patients with histologically
transformed B-cell non-Hodgkin lymphomas. A Norwegian multi
centre phase II study. Br J Haematol. 2011;152:600-610.
20. Friedberg JW, Neuberg D, Gribben JG, et al. Autologous bone marrow
transplantation after histologic transformation of indolent B cell malignancies. Biol Blood Marrow Transplant. 1999;5:262-268.
21. Kuruvilla J, Chen B, MacDonald DA, et al. Salvage chemotherapy (SC)
and autologous stem cell transplantation (ASCT) for transformed
indolent lymphoma (TR): A subgroup analysis of NCIC CTG LY12.
Hematol Oncol. 2013;31(Suppl 1). Abstr 64.
22. Ramadan KM, Connors JM, Al-Tourah AJ, et al. Allogeneic SCT for
relapsed composite and transformed lymphoma using related and
unrelated donors: long-term results. Bone Marrow Transplant. 2008;42:
601-608.
23. Ramadan KM, Connors JM, Al-Tourah A, et al. Autologous stem cell
transplantation is superior to myeloablative allogeneic SCT as a salvage
therapy for patients with refractory/relapsed transformed lymphoma.
Blood. 2008;112:4459.
24. Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic
hematopoietic cell transplantation in relapsed, refractory, and
1818
25.
26.
27.
28.
D. Villa et al. / Biol Blood Marrow Transplant 20 (2014) 1813e1818
transformed indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:
211-217.
Villa D, Crump M, Keating A, et al. Outcome of patients with transformed indolent non-Hodgkin lymphoma referred for autologous
stem-cell transplantation. Ann Oncol. 2013;24:1603-1609.
Cwynarski K, van Biezen A, de Wreede L, et al. Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic
leukemia (Richter’s syndrome): A retrospective analysis from the
Chronic Lymphocytic Leukemia Subcommittee of the Chronic Leukemia Working Party and Lymphoma Working Party of the European
Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30:
2211-2217.
Rodriguez J, Keating MJ, O’Brien S, et al. Allogeneic haematopoietic
transplantation for Richter’s syndrome. Br J Haematol. 2000;110:
897-899.
Tsimberidou AM, O’Brien S, Khouri I, et al. Clinical outcomes and
prognostic factors in patients with Richter’s syndrome treated with
29.
30.
31.
32.
33.
chemotherapy or chemoimmunotherapy with or without stem-cell
transplantation. J Clin Oncol. 2006;24:2343-2351.
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international
workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol.
1999;17:1244.
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481.
Bains P, Al Tourah A, Campbell BA, et al. Incidence of transformation to
aggressive lymphoma in limited-stage follicular lymphoma treated
with radiotherapy. Ann Oncol. 2013;24:428-432.
Al-Tourah AJ, Savage KJ, Gill KK, et al. Addition of rituximab to CHOP
chemotherapy significantly improves survival of patients with transformed lymphoma. Blood. 2007;110:790.
Tan D, Rosenberg SA, Lavori P, et al. Improved prognosis after histologic
transformation (HT) of follicular lymphoma: the Stanford experience
1960-2003. Ann Oncol. 2008;19(Suppl 4). iv111.