Biol Blood Marrow Transplant 22 (2016) 1543e1551

Biology of Blood and

Marrow Transplantation
journal homepage: www.bbmt.org

Reviews

Allogeneic Hematopoietic Cell Transplantation as Curative

Therapy for Patients with Non-Hodgkin Lymphoma:
Increasingly Successful Application to Older Patients
Timothy S. Fenske 1, *, Mehdi Hamadani 1, 2, Jonathon B. Cohen 3, Luciano J. Costa 4, Brad S. Kahl 5,
Andrew M. Evens 6, Paul A. Hamlin 7, Hillard M. Lazarus 8, Effie Petersdorf 9,
Christopher Bredeson 10
1
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
2
Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin
3
Department of Hematology and Medical Oncology, Emory University, Winship Cancer Institute, Atlanta, Georgia
4
Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama
5
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri
6
Division of Hematology/Oncology, Tufts Medical Center, Boston, Massachusetts
7
Department of Medicine, Memorial Sloan Kettering Cancer Center, and Department of Medicine, Weill Medical College of Cornell University, New York Presbyterian
Hospital, New York, New York
8
Division of Hematology-Oncology, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio
9
Division of Medical Oncology, University of Washington School of Medicine, and Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle,
Washington
10
Blood and Marrow Transplant Program, Ottawa Hospital Research Institute at University of Ottawa, Ottawa, Ontario, Canada

Article history: a b s t r a c t
Received 6 February 2016 Non-Hodgkin lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with widely varying
Accepted 21 April 2016 biological, histological, and clinical features. For the B cell NHLs, great progress has been made due to the
addition of monoclonal antibodies and, more recently, other novel agents including B cell receptor signaling
Key Words: inhibitors, immunomodulatory agents, and proteasome inhibitors. Autologous hematopoietic cell trans-
Allogeneic hematopoietic cell plantation (auto-HCT) offers the promise of cure or prolonged remission in some NHL patients. For some
transplantation patients, however, auto-HCT may never be a viable option, whereas in others, the disease may progress
Non-Hodgkin lymphoma
despite auto-HCT. In those settings, allogeneic HCT (allo-HCT) offers the potential for cure. Over the past 10 to
Elderly
15 years, considerable progress has been made in the implementation of allo-HCT, such that this approach
Reduced-intensity conditioning
now is a highly effective therapy for patients up to (and even beyond) age 75 years. Recent advances in
conventional lymphoma therapy, peritransplantation supportive care, patient selection, and donor selection
(including the use of alternative hematopoietic cell donors), has allowed broader application of allo-HCT to
patients with NHL. As a result, an ever-increasing number of NHL patients over age 60 to 65 years stand to
benefit from allo-HCT. In this review, we present data in support of the use of allo-HCT for patients with
diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. These histologies account for
a large majority of allo-HCTs performed for patients over age 60 in the United States. Where possible, we
highlight available data in older patients. This body of literature strongly supports the concept that allo-HCT
should be offered to fit patients well beyond age 65 and, accordingly, that this treatment should be covered by
their insurance carriers.
Ó 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION
In many cases of high-risk non-Hodgkin lymphoma
(NHL), the sole potentially curative option for patients
(regardless of age) remains allogeneic hematopoietic
Financial disclosure: See Acknowledgments on page 1549. cell transplantation (allo-HCT). With recent advances
* Correspondence and reprint requests: Timothy S. Fenske, MD, Medical
in pretransplantation, peritransplantation, and post-
College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226.
E-mail address: [email protected] (T.S. Fenske).
transplantation care, allo-HCT can now be successfully

http://dx.doi.org/10.1016/j.bbmt.2016.04.019
1083-8791/Ó 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1544 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551

applied to a wider population of patients, including those [1], or biologically identified, for example the “double-hit”
with advanced age. Although it is true that advanced age and “triple-hit” lymphomas (ie, those with MYC and BCL2
does increase the risk of transplantation-related complica- and/or BCL6 translocations). Particularly for double- and
tions and nonrelapse mortality (NRM), allo-HCT still often triple-hit lymphomas, standard frontline therapies are
represents the sole realistic option for cure in many older ineffective for providing long-term remission, and cure is
patients. After careful consideration of risks, benefits, and rarely achieved in the relapsed and refractory settings. Thus,
alternatives, an increasing number of patients into their 70s selecting the optimal therapy for such patients remains a
are electing to undergo allo-HCT. great challenge [5,6].
In this report, we begin by reviewing 3 B cell NHL sub-
types: diffuse large B cell lymphoma (DLBCL), follicular Auto-HCT for DLBCL
lymphoma (FL), and mantle cell lymphoma (MCL). These 3 High-dose chemotherapy with auto-HCT exploits the
lymphoma histologies accounted for 73% of allo-HCTs per- steep dose-response curve of some chemotherapy agents, by
formed in patients over age 60 in the United States between eradicating disease that could not be eliminated by con-
2010 and 2014 (Personal communication, Mehdi Hamadani, ventional chemotherapy doses. Two decades ago, a ran-
Center for International Blood and Marrow Transplant domized trial conducted in patients with relapsed aggressive
Research, April 18, 2016). For each subtype, we first provide a lymphoma with chemosensitive disease showed a 53% 5-
brief overview of the use of nontransplantation frontline year survival with auto-HCT versus 32% with continuation
therapies. We next briefly review outcomes for autologous of conventional chemotherapy [7]. Even in the rituximab era,
hematopoietic cell transplantation (auto-HCT), and discuss some patients with disease relapse will be long-term survi-
the available data supporting the use of allo-HCT. Finally, we vors after proper second-line therapy and auto-HCT [8];
present data specifically supporting allo-HCT in elderly pa- however, significantly worse results are expected in patients
tients with lymphoma. who never achieve complete response (CR) with frontline
therapy, who have a short duration of CR, or relapse with a
DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) high IPI. For example, in the CORAL trial, fewer than 25% of
Overview of DLBCL and Nontransplant treatment patients who relapsed within 1 year of diagnosis achieved
Options long-term disease-free survival with auto-HCT [9].
The most common type of aggressive NHL, DLBCL Investigations of strategies designed to improve on auto-
encompasses several clinical-pathological entities. Although HCT, such as modifying the transplant preparative regimen
risk factors include HIV infection, solid organ trans- with the addition of radioimmunotherapy to the chemo-
plantation, and autoimmune disorders, most cases are spo- therapy backbone [10] or the use of post-transplantation
radic and occur predominantly in individuals age >60 years maintenance therapy [11], have not proven beneficial in
with no obvious predisposing factors. Overall, 60% of those relapsed/refractory (R/R) DLBCL. Auto-HCT remains the
affected will be cured with chemoimmunotherapy. Clinical standard of care for chemosensitive R/R DLBCL, but better
factors such as the National Comprehensive Cancer Network approaches are needed for patients who experience relapse
(NCCN) International Prognostic Index (NCCN-IPI), however, after auto-HCT or for whom auto-HCT is not an option due to
delineate a wide range of results, identifying groups with a insufficient chemosensitivitity.
likelihood of 5-year survival ranging from as high as 96% to as
low as 38% [1,2]. A greater understanding of biology and Allo-HCT for DLBCL
genetics has refined prognostic markers with potential Recent studies of allo-HCT involving at least 40 patients
therapeutic implications, such as the putative cell of origin with DLBCL are listed in Table 1. Allo-HCT provides the
(defined by gene expression profile or immunohistochem- theoretical advantage of a tumor-free graft and the benefit of
istry) [3,4], and translocation or overexpression of the MYC a graft-versus-lymphoma (GVL) effect. This GVL effect has
oncogene [5]. been well demonstrated by the fact that some patients who
Despite these advances, several disease subsets repre- experience relapse after auto-HCT will attain cure with allo-
sent high-risk disease, clinically defined by the NCCN-IPI HCT. Furthermore, the use of donor lymphocyte infusion,

Table 1
Recent Studies Reporting Outcomes of Allo-HCT for DLBCL (>40 Patients)

Study No. of Previous Conditioning (%) Median Age, NRM/TRM, % (yr) Relapse, % (yr) OS, % (yr)
Patients Auto-HCT, % yr (Range)
Thomson et al., 2009 [12] 48 69 RIC (100) 46 (23-64) 32 (4) 33 (4) 48 (4)
Sirvent et al., 2010 [13] 68 79 RIC (100) 48 (17-66) 23 (1) 41 (2) 49 (2)
Lazarus et al., 2010 [14] 79* 0 MAC (100) 46 (21-59) 43 (3) 33 (3) 26 (3)
van Kampen et al., 2011 [15] 101 100 MAC (37) 46 (18-66) 28 (3) 30 (3) 52 (3)
RIC (63)
Rigacci et al., 2012 [16] 165 100 MAC (30) 43 (16-65) 19-32 (2) NR 39 (5)
RIC (70)
Bacher et al., 2012 [17] 396 32 MAC (42) 54 (18-66) 36-56 (5) 26-40 (5) 18-26 (5)
RIC (58)
Hamadani et al., 2013 [18] 533y 25 MAC (58) 46 (19-66) 53 (3) 28 (3) 19 (3)
RIC (42) 53 (20-70) 42 (3) 35 (3) 28 (3)
Fenske et al., 2015 [19] 503 100 MAC (25) 52 (19-72) 31 (5) 40 (5) 34 (5)
RIC (75)

NR indicates not reported.

* Analysis restricted to patients undergoing MA allo-HCT as first transplantation.
y
Included 85% DLBCL and 15% FL grade 3; all patients had chemoresistant disease pretransplantation.
 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551 1545

withdrawal of immune suppression, or the combination patients who have good potential to benefit from allo-HCT
provides a GVL effect in DLBCL after allo-HCT, leading to cure (3-year OS of 43%) [19].
in some cases [12,20,21]. Allo-HCT, however, presents chal-
lenges including donor availability, the need for prolonged
immunosuppression, and an increased risk of early Summary: DLBCL
treatment-related mortality (TRM) owing to toxicity of the These data indicate that medically appropriate patients
conditioning regimen, graft-versus-host disease (GVHD), and with DLBCL whose disease relapses after auto-HCT have the
infectious complications. Progress in addressing these chal- clearest indication for allo-HCT and potentially can be cured.
lenges has been made in recent years. In this setting, patients should receive RIC preferentially,
In the past, allo-HCT used myeloablative conditioning ideally after conventional debulking therapy. Other subsets
(MAC) to eliminate maximal tumor and permit engraftment of patients who may benefit from allo-HCT are patients
by eliminating the host immune system. No prospective known to have a low chance of cure with auto-HCT, as
trials comparing auto-HCT versus MAC allo-HCT for R/R identified by use of the second-line IPI, failure to attain CR
DLBCL have been undertaken to date. A large retrospective using initial therapy, relapse <12 months after chemo-
analysis by the Center for International Blood and Marrow immunotherapy, or NHL refractory to second- and third-line
Transplant Research (CIBMTR) including 837 auto-HCTs and chemotherapy [9,18,20,26]. The recently developed CIBMTR
79 allo-HCTs performed between 1995 and 2003 demon- prognostic model described above can guide decision mak-
strated higher TRM, NRM, and overall mortality in the ing [19]. Other appropriate indications include (1) patients in
allo-HCT group, with no decrease in the risk of disease pro- whom auto-HCT is not feasible, either by failure to obtain an
gression [14]; however; the subjects who underwent allo- adequate autologous graft for transplantation or coexistence
HCT were more likely to have high-risk disease features, of intrinsic bone marrow disease, particularly myelodys-
including later disease stage, to have received more previous plastic syndrome; (2) DLBCL transformed from an indolent
chemotherapy regimens, and to have resistant disease. B cell malignancy relapsing after anthracycline-containing
Despite such limitations, reviewing the literature on allo- therapy, or a failed auto-HCT; and (3) double-hit DLBCL.
HCT reveals a consistent message that long-term overall
survival (OS) in the 20% to 50% range is possible (Table 1). The
25% to 30% rate of NRM remains the greatest drawback. Less- FOLLICULAR LYMPHOMA (FL)
intensive preparative regimens (termed reduced-intensity Overview of FL and Nontransplant treatment
conditioning [RIC]) have been implemented in recent years. Options
Retrospective comparisons between MAC and RIC show FL is the most common subtype of indolent NHL, ac-
reduced NRM, at the expense of some increase in disease counting for roughly 20% of all cases of NHL. Unlike patients
relapse, but producing long-term OS rates comparable to with aggressive NHL, nearly all patients who complete in-
those for MAC [17,18]. Most allo-HCTs for DLBCL are now duction therapy will eventually relapse and require addi-
performed using lower-intensity regimens, which also per- tional lines of therapy. Furthermore, although OS is
mits the use of this procedure in older patients who are prolonged for many patients, with standard therapies FL
otherwise good candidates but previously would have been remains incurable for the vast majority. The Follicular Lym-
excluded from MAC allo-HCT because of age [17]. The phoma International Prognostic Index (FLIPI) incorporates
expanding use of allo-HCT in older patients is evidenced by clinically based features and identifies a subgroup at high
the fact that the more recent studies listed in Table 1 include risk for early disease-related death [27]. Approximately one-
patients 65 to 72 years of age. One recent study focusing on quarter of all patients with FL fall into this poor-risk category
the use of allo-HCT in patients with NHL in their 60s and (ie, 3 risk factors), which has an estimated 5-year OS of only
early 70s found no major increase in NRM for such patients 53%.
[22]. A proportion of patients may be safely observed without
treatment until the development of symptomatic progres-
Allo-HCT for DLBCL following failed auto-HCT sive disease, bulky adenopathy, cytopenia, organ obstruction,
Roughly 30% to 40% of DLBCL auto-HCT recipients ulti- or malignant fluid collection [28]. Patients who require
mately will experience relapse or progression of DLBCL and therapy but otherwise have a low tumor burden may be
cannot be cured with intensification of chemotherapy. As managed with single-agent rituximab [29]; however, many
noted above, because of the GVL effect in DLBCL, such pa- patients require combination chemoimmunotherapy.
tients are often considered for allo-HCT after a failed previ- Currently, bendamustine-rituximab may be a preferred
ous auto-HCT [15,16,19,23]. These studies report TRM/NRM frontline approach in FL with a high tumor burden, with
rates of 17% to 31% but 3- to 5-year OS rates of 34% to 52%. In improved progression-free survival (PFS) (median, not
the most recent and largest study, from the CIBMTR, 503 reached versus 41 months; P ¼ .0072) and decreased toxicity
patients were analyzed. At 3 years, NRM was 30%, with a compared with R-CHOP (rituximab, cyclophosphamide,
progression/relapse rate of 38% and OS of 37%, a reasonable doxorubicin, vincristine, and prednisone) [30].
result given that the median survival typically seen in this There is no standard therapy for R/R FL; readily available
population is in the 3- to 10-month range [24,25]. In multi- options include anti-CD20 immunotherapies, combination
variate analysis, advanced age was not a prognostic factor, chemotherapy, radioimmunotherapy, the oral PI3 kinase
indicating that chronologic age should not be the key factor idelalisib, immunomodulatory drugs (lenalidomide), and the
used to determine allo-HCT eligibility. A prognostic model Bruton tyrosine kinase inhibitor ibrutinib [31]. More inten-
was constructed using Karnofsky Performance Status <80, sive treatments often are considered for high-risk patients,
time from auto-HCT to allo-HCT of <1 year, and chemo- especially those who relapse early after induction therapy,
resistant disease as adverse factors. This CIBMTR model fa- because relapse within 2 years of initial therapy is associated
cilitates the identification of high-risk patients unlikely to with a 5-year OS of only 50% [32]. In this context, auto-HCT
benefit from allo-HCT (3-year OS of 14%), as well as low-risk and allo-HCT can provide for long-term survival in R/R FL.
1546 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551

Auto-HCT for FL cyclophosphamide and a matched related donor graft. The 3-

Auto-HCT for FL in first remission year event-free survival was 75%, and 3-year OS was 81%; 3
The data to support auto-HCT for FL in first remission are subjects relapsed. A second prospective study of 47 patients
limited. Prospective randomized trials comparing chemo- conducted at M.D. Anderson Cancer Center used RIC condi-
therapy with auto-HCT in first complete remission have tioning with fludarabine, cyclophosphamide, and rituximab
generally shown a PFS benefit, but not an OS benefit, in favor [51]. The median 5-year PFS and OS were both 85%; 7 pa-
of up-front auto-HCT [33-36]. Benefit in terms of improved tients died, most from infectious complications. Another
lymphoma-specific survival appears to be offset by a report combined 2 prospective multicenter Spanish trials in
decrease in survival owing to secondary malignancies, such 37 patients who received fludarabine/melphalan RIC
as myelodysplastic syndrome and acute myelogenous leu- regimen [42]. The relapse incidence was only 8%, but NRM
kemia. As a result, auto-HCT is not recommended for was as high as 71% in patients with active disease before allo-
consolidation of remission after first-line therapy for low- HCT. For patients in CR before transplantation, the 4-year OS
grade FL. was 71%, comparable to those reported in other studies. In a
prospective study from the United Kingdom that enrolled 82
Auto-HCT for R/R FL consecutive patients with FL treated with fludarabine,
Although auto-HCT can produce prolonged remissions, it melphalan, and alemtuzumab RIC, NRM was 15%, relapse rate
typically is not viewed as curative therapy in R/R FL. Pro- was only 26% at 4 years, and OS was 76% at 4 years [43].
spective studies are lacking, although a randomized study Finally, another prospective multicenter study in 46 patients
(n ¼ 89) from the pre-rituximab era, which closed early due with FL coordinated by the Fred Hutchinson Cancer Research
to poor accrual, showed improved 2-year PFS and 4-year OS Center [40] reported a high 42% rate of NRM, driven in large
in auto-HCT recipients compared with patients receiving part by the use of mismatched unrelated allografts. The
standard chemotherapy [37]. A review of 2 French studies relapse rate at 3 years was low, at 14%.
demonstrated that rituximab at relapse appeared to have a
more prominent impact on event-free survival and OS Allo-HCT for R/R FL: retrospective studies
compared with receipt of auto-HCT [38]. At least 9 additional The NCCN compared outcomes in 48 allo-HCT and auto-
single-center retrospective studies and large registry studies HCT recipients [45]. The allo-HCT recipients had a 3-year
of R/R FL have demonstrated PFS in the 30% to 60% range at 5 NRM of 26%; in a multivariable analysis, allo-HCT was
to 10 years, although not all of the patients in these series associated with an increased risk of death compared with
were treated with rituximab [39]. Considering that a large auto-HCT (P ¼ .002). These data should be interpreted with
majority of patients with FL relapse after auto-HCT, this caution, however, as the group of FL allo-HCT recipients
approach cannot be considered a curative intervention for were a highly select and high-risk group. In contrast, a
most patients with FL. However, auto-HCT is a reasonable recent and larger analysis by the CIBMTR indicates that
consideration and may provide prolonged disease control in long-term remission is feasible in a significant number of R/
high risk FL patients who are not candidates for allo-HCT. R FL patients who receive allo-HCT, and that patients who
do not die early in the post-transplantation course have
Allo-HCT for FL prolonged survival compared with patients receiving auto-
There are no randomized prospective trials or retrospec- HCT. Among 268 relapsed patients with grade 1 to 2 FL
tive studies to support the application of allo-HCT as who underwent RIC allo-HCT, the 5-year NRM was 26%., the
consolidation therapy for FL in first remission. However, probability of disease progression at 5 years was 20%, and
numerous prospective as well as retrospective studies sup- the 5-year PFS was 41%, representing a subset of patients
port the use of allo-HCT in R/R FL. Outcomes reported by who are likely cured of their disease. The 5-year OS was 66%,
selected studies investigating allo-HCT in R/R FL are pre- and among 24-month survivors, the subsequent risk of
sented in Table 2. death was decreased in patients undergoing allo-HCT
compared with those undergoing auto-HCT (RR, 2.09;
Allo-HCT for R/R FL: prospective studies P ¼ .04) [47]. A recent retrospective study from Memorial
Shea et al. [50] reported a prospective study of 16 patients Sloan-Kettering compared outcomes for patients with R/R
receiving RIC allo-HCT conditioned with fludarabine/ FL undergoing auto-HCT versus allo-HCT in the post-

Table 2
Studies Evaluating Allo-HCT in Relapsed/Refractory FL (>30 Patients)

Study No. of Conditioning (%) Age, yr, TRM/NRM, Relapse, OS, % (yr) Comments
Patients Median (Range) % (yr) % (yr)
Rezvani et al., 2008 [40] 46 RIC 54 (33-66) 42 (3) 14 (3) 52 (3) Prospective
Hari et al., 2008 [41] 208 MAC (58) 44 (27-70) 23 (1) 8-17 (3) 62-71 (3) Retrospective (CIBMTR)
RIC (42) 51 (27-70)
Piñana et al., 2010 [42] 37 RIC 50 (34-62) 37 (4) 8 (4) 57 (4) Prospective
Thomson et al., 2010 [43] 82 RIC 45 (26-65) 15 (4) 26 (4) 76 (4) Prospective
Khouri et al., 2012 [44] 47 RIC 53 (33-68) 15 (8) 4 (8) 85 (8) Prospective; 45/47 MRD
Evens et al., 2013 [45] 48 NR 50 (27-64) 24 (3) 16 (3) 61 (3) Retrospective (NCCN)
Robinson et al., 2013 [46] 149 RIC 51 (33-66) 22 (3) 20 (5) 67 (5) Retrospective (EBMT)
Klyuchnikov et al., 2015 [47] 268 RIC 52 (27-74) 26 (5) 20 (5) 66 (5) Retrospective (CIBMTR);
grade 1 and 2 FL
Klyuchnikov et al., 2015 [48] 70 RIC 53 (36-64) 27 (5) 20 (5) 54 (5) Retrospective (CIBMTR);
grade 3 FL
Yano et al., 2015 [49] 46 RIC 48 (34-66) 23 (5) 15 (5) 81 (5) Retrospective (Japan)

MRD indicates matched related donor.

 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551 1547

rituximab era. In a subgroup analysis performed in patients Historically, using conventional frontline therapy such as
with a remission duration of <12 months before salvage R-CHOP, the median duration of remission was only 12 to
therapy, 3-year event-free survival was 42% with auto-HCT 18 months [56]. Recently, however, incorporation of such
versus 80% with allo-HCT, suggesting that patients with a agents as bortezomib, bendamustine, and lenalidomide into
very short first remission (<1 year) may be better served first-line therapy have improved on this result, with PFS in
with an allo-HCT approach [52]. the 27- to 35-month range or longer [30,57-59]. Intensive
regimens like R-Hyper-CVAD (rituximab, fractionated
Allo-HCT for grade 3 FL cyclophosphamide, vincristine, doxorubicin, and dexameth-
A recent report from the CIBMTR examined the outcomes asone alternating with methotrexate and cytarabine)
of 61 patients who underwent RIC allo-HCT for grade 3 FL without subsequent consolidation led to impressive PFS in
[48]. At 5 years, NRM was 27% and OS 54%, indicating that some reports, but toxicity concerns have dampened enthu-
grade 3 histology should not be an exclusion factor for siasm for this approach [60-62].
allo-HCT, and that RIC can offer long-term survival for pa- Given the relatively short remissions observed in MCL,
tients with grade 3 histology. investigators have tested the concept of maintenance ritux-
imab after conventional frontline therapies. The median
duration of first remission has improved to the 3- to 5-year
Summary: FL
range. As a result, rituximab maintenance is a reasonable
Although auto-HCT is not considered a curable interven-
option for elderly patients with MCL who are not candidates
tion for most patients, a subset (w30% to 35%) may enjoy
for HCT [63,64].
long-term (>5-year) remissions with this therapy, justifying
its use in second or third remission. Furthermore, given the
Auto-HCT for MCL
development of less-toxic novel therapeutic strategies in the
Auto-HCT for MCL in first remission
modern era, the use of auto-HCT may decline in the coming
In the pre-rituximab era, the poor prognosis seen in
years. It should be noted that these novel strategies are not
relapsed MCL motivated the European MCL Network to
currently known to be curative. In contrast, allo-HCT
conduct a randomized, prospective postremission trial
repeatedly has been shown to be a curative therapy for a
comparing auto-HCT with IFNa maintenance [65]. Auto-HCT
significant subset of patients with R/R FL. Although the rate
demonstrated superior PFS; however, no OS benefit was
of early death is increased in patients with FL receiving allo-
seen, possibly due to crossing over of the IFNa-treated pa-
HCT owing to increased NRM, the studies cited above
tients to subsequently receive auto-HCT off protocol. Although
demonstrate excellent long-term outcomes in those surviv-
similar prospective randomized data in the rituximab era are
ing the early period. With the increasing application of RIC
not available, several large prospective phase 2 trials applying
allo-HCT, and continued improvement in supportive care,
up-front auto-HCT after various intensive induction regimens
NRM rates likely will continue to decline for well-selected
have yielded median PFS durations in the 5- to 7-year range
patients with FL who receive expert supportive care. Such
[66-71]. Despite the lack of randomized, controlled data
patients can expect a reasonable chance of being cured.
demonstrating a survival benefit with auto-HCT as consoli-
These observations apply to patients over age 65 years, for
dation in first remission, many clinicians have adopted this
whom outcomes with RIC are comparable to, or only mini-
approach. Certain patients, such as those not in CR at the time
mally less favorable than, those in the 55- to 64-year age
of up-front auto-HCT [72], those with minimal residual dis-
group [22].
ease pretransplantation [73], or those with a high-risk MIPI
score [55,68,74], fare considerably less well with upfront auto-
MANTLE CELL LYMPHOMA (MCL) HCT consolidation, underscoring the need for novel modal-
Overview of MCL and Nontransplant treatment ities to consolidate first remission for such patients.
Options
MCL comprises w6% of newly diagnosed cases of NHL. Auto-HCT for relapsed/refractory MCL
The median age at diagnosis is in the late 60s, with a 4:1 male Initial retrospective studies, including a European Society
predominance. Patients often present in an advanced disease of Blood and Marrow Transplantation (EBMT) study [75],
stage, along with extranodal involvement. Modern chemo- have suggested that auto-HCT may have limited value in
immunotherapies alone, or as induction followed by auto- relapsed and refractory patients. More recent studies, how-
HCT in first remission, undoubtedly have improved patient ever, including a large retrospective study from the CIBMTR,
outcomes; however, disease relapse eventually occurs in have indicated that durable remissions in the 2- to 4-year
most patients [53]. range may be seen in selected patients with MCL whose
Although variables such as histology (eg, blastoid disease remains chemosensitive [72,76]. Therefore, in pa-
morphology), tumor proliferation index, cytogenetics, and tients with relapsed chemosensitive MCL who are not can-
gene expression profiling have prognostic value in MCL, their didates for potentially curative allo-HCT (due to
clinical applications for risk-adapted treatment remains comorbidities, donor availability, etc), consolidation with an
limited [45]. The MCL International Prognostic Index (MIPI) auto-HCT can be offered, with the understanding that this
is a commonly used risk-stratification score based on patient therapy is not curative. It remains to be seen whether auto-
age, performance status, serum lactate dehydrogenase, and HCT will remain part of the treatment paradigm for R/R
white blood cell count at diagnosis, with/without Ki-67 MCL in the era of new and novel agents.
proliferation index, that classifies MCL into low-, interme-
diate-, and high-risk groups, with median OS ranging from Allo-HCT for MCL
29 months to > 5 years [54]. This index also has been vali- Allo-HCT for MCL in first remission
dated to predict outcomes after auto-HCT [55], but has not Although adoptive immunotherapy in the form of allo-
yet been validated as a tool to direct optimal consolidation HCT is a potentially curative option for patients with MCL,
therapies in patients responding to frontline therapies. there are no prospective data assessing this approach in first
1548 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551

Table 3
Studies Evaluating Allo-HCT in Relapsed/Refractory MCL (>30 Patients)

Study No. of Conditioning (%) Age, yr, TRM/NRM, Relapse, OS, % (yr)
Patients Median (Range) % (yr) % (yr)
Maris et al., 2004 [77] 33 RIC (100) 53 (33-70) 9 (2) 16 (2) 65 (2)
Cook et al., 2010 [78] 70 RIC (100) 52 (25-69) 18 (3) 65 (5) 37 (5)
Le Gouill et al., 2012 [79] 70 RIC (100) 56 (33-67) 32 (2) 18 (2) 53 (2)
Hamadani et al., 2013 [80],* 202 MAC (37) 54 (27-69) 38-43 (1) 32-33 (3) 25-30 (3)
RIC (63) 59 (42-75)
Fenske et al., 2014 [72],y 88 RIC (100) 58 (26-75) 17 (1) 38 (5) 31 (5)
Krüger et al., 2014 [81] 33 MAC (21) 59 (33-69) 24 (5) 15 (5) 73 (5)
RIC (79)

* Included only patients with refractory disease.

y
Excluded patients with refractory disease.

remission. Registry data from the CIBMTR examining the role with curative potential. With the widespread implementa-
of allo-HCT versus auto-HCT in first CR or partial remission tion of RIC, properly selected patients with MCL who receive
showed no benefit in terms of PFS (55% versus 52% at 5 years) expert supportive care have a reasonable chance of being
or OS (62% versus 61% at 5 years); however, early allograft cured with allo-HCT. This also applies to patients over age 65,
was associated with a significantly higher NRM (25% versus in whom outcomes with RIC are comparable to those in the
3% at 1 year) [72]. As a result, the use of allo-HCT in che- 55- to 64-year age group [22].
mosensitive patients with MCL in first remission generally is
not recommended. Early use of allo-HCT can be considered in ALLO-HCT IN OLDER PATIENTS WITH LYMPHOMA
selected patients for whom the chance for success with auto- Tables 1-3 list numerous key studies of allo-HCT in DLBCL,
HCT is poor, such as those with high MIPI score or not in CR FL, and MCL, several of which include patients up to age 70 to
before transplantation. It has been hypothesized that in such 75 years. A recent registry study by McClune et al. [22]
patients, outcomes might be improved by early allografting. specifically analyzed outcomes in 82 patients age 65 un-
This approach would not yet be considered standard care by dergoing allo-HCT for NHL. Although 100-day NRM was not
most clinicians, but warrants prospective investigation. significantly different, NRM at 1 year was higher in this older
age group (34%) compared with 2 younger populations, 40 to
Allo-HCT for R/R MCL 54 years (27%) and 55 to 64 years (22%). Relapse rates at
As shown in Table 3, evidence from several single-center 3 years were similar across the 3 age groups (28% to 33%). Not
studies and large transplantation registries have established surprisingly, OS was highest in the 40- to 54-year age group;
that allo-HCT is the sole potentially curative modality for R/R however, the 65-year age group fared reasonably well, with
MCL, with 35% to 45% of patients disease-free (and likely a 3-year OS of 39%. Nonetheless, it should be emphasized
cured) at 3 years post-transplantation [72,77-81]. Chemo- that in individual patients over age 65, the real question
sensitive disease and adequate performance status are pre- should be not whether allo-HCT outcomes are comparable to
dictive of improved allo-HCT outcomes. In recent years, the those in patients under age 65, but rather whether allo-HCT
wider adoption of RIC regimens has extended the availability offers the best reasonable chance for long-term remission or
of allo-HCT to elderly patients and patients with medical cure for that patient, when considering all treatment options.
comorbidities. Nonetheless, the prognosis remains particu- Owing in part to the advances in patient selection, donor
larly poor in the challenging subset of patients with selection, pretransplantation lymphoma therapy, and peri-
chemotherapy-unresponsive MCL. A large CIBMTR analysis transplantation supportive care, older patients are increas-
restricted to such chemorefractory patients showed that ingly undergoing allo-HCT. As shown in Figure 1, data from
approximately one-quarter gain durable disease control with the CIBMTR show increasing use over time of allo-HCT for
allo-HCT, likely due to a clinically relevant GVL effect [80]. No NHL in patients age >60 years. For example, the percentage
benefit of MAC was seen even in this high-risk cohort of of patients age >60 undergoing allo-HCT for DLBCL, FL, and
patients. Thus, in otherwise healthy patients with relapsed or
refractory MCL and an available sibling or adult unrelated
donor, RIC allo-HCT with curative intent is a reasonable
therapeutic option. In medically fit patients without signifi-
cant comorbidities, advanced age should not be considered a
contraindication.

Summary: MCL
Currently, both auto-HCT and allo-HCT play important
roles in the management of MCL. Auto-HCT is not considered
curative therapy for MCL, although an intensive induction
and consolidation from auto-HCT may provide many pa-
tients with remissions that can last 6 to 8 years or longer.
Selected patients with MCL who did not undergo auto-HCT
as part of frontline therapy also may benefit from auto-HCT
later in the disease course. Despite the recent emergence of Figure 1. Increase in proportion of NHL patients over age 60 undergoing allo-
several exciting new agents, for the vast majority of patients HCT in the United States between 1996 and 2014. Data provided by the Center
with R/R MCL, allo-HCT remains the sole treatment option for International Blood and Marrow Transplant Research.
 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551 1549

MCL rose from 12%, 10%, and 23%, respectively, in 2001 to ACKNOWLEDGMENTS
2005 to 31%, 28%, and 48%, respectively in 2011 to 2014 Financial disclosure: The authors have no financial
(personal communication, CIBMTR). These figures clearly disclosures relevant to this work to report.
show that allo-HCT is an important therapeutic option for Conflict of interest statement: The authors report no
DLBCL, FL and MCL, even in older patients. In recent years, conflicts of interest relevant to this work to report.
alternative donor transplantation (umbilical cord blood or
haploidentical marrow) has become more widespread, with
recent studies reporting outcomes that compare favorably to REFERENCES
1. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International
those using matched unrelated donors [82,83]. The hap- Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell
loidentical approach, with post-transplantation cyclophos- lymphoma treated in the rituximab era. Blood. 2014;123:837-842.
phamide, has been successfully applied to patients with 2. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab
compared with CHOP alone in elderly patients with diffuse large-B-cell
lymphoma up to age 75, with a reported 1-year NRM of
lymphoma. N Engl J Med. 2002;346:235-242.
10% to 15% across all age groups from 50 to 75 years, and a 3- 3. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling
year survival of approximately 50% [82,84]. With the growing to predict survival after chemotherapy for diffuse large-B-cell lym-
use and success of alternative donor transplantation, it is phoma. N Engl J Med. 2002;346:1937-1947.
4. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the
expected that an even larger number of older patients will be molecular classification of diffuse large B-cell lymphoma by immuno-
allo-HCT candidates, because in many cases such patients do histochemistry using a tissue microarray. Blood. 2004;103:275-282.
not have a matched sibling in sufficiently good health to 5. Cheah CY, Oki Y, Westin JR, Turturro F. A clinician’s guide to double-hit
lymphomas. Br J Haematol. 2015;168:784-795.
serve as a donor. 6. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen
Based on the foregoing data, it is becoming increasingly and stem cell transplantation on outcomes in double-hit lymphoma: a
clear that allo-HCT is in fact feasible in older patients. Thus, multicenter retrospective analysis. Blood. 2014;124:2354-2361.
7. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow
transplantation clinicians will be increasingly challenged to transplantation as compared with salvage chemotherapy in relapses of
consider allo-HCT for these older patients. On an individual chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;
patient level, the decision to proceed to transplantation re- 333:1540-1545.
8. Hamadani M, Hari PN, Zhang Y, et al. Early failure of frontline
quires a careful consideration of patient issues (comorbid-
rituximab-containing chemo-immunotherapy in diffuse large B cell
ities, performance status), disease factors (histology and lymphoma does not predict futility of autologous hematopoietic cell
biological features of the lymphoma, clinical aggressiveness, transplantation. Biol Blood Marrow Transplant. 2014;20:1729-1736.
9. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with
disease burden), donor factors, and psychosocial factors.
autologous transplantation for relapsed large B-cell lymphoma in the
These considerations are of particular importance in older rituximab era. J Clin Oncol. 2010;28:4184-4190.
patients, in whom the therapeutic window for transplant 10. Vose JM, Carter S, Burns LJ, et al. Phase III randomized study of ritux-
may be narrow and the risk for toxicity and disability post- imab/carmustine, etoposide, cytarabine, and melphalan (BEAM)
compared with iodine-131 tositumomab/BEAM with autologous he-
transplantation may be higher. With this in mind, it will be matopoietic cell transplantation for relapsed diffuse large B-cell lym-
very important to prospectively collect quality of life data in phoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013;31:
elderly patients undergoing allo-HCT for NHL, if allo-HCT 1662-1668.
11. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance
becomes a covered indication in these patients. therapy after autologous stem-cell transplantation in patients with
relapsed CD20(þ) diffuse large B-cell lymphoma: final analysis of the
collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;
30:4462-4469.
12. Thomson KJ, Morris EC, Bloor A, et al. Favorable long-term survival
SUMMARY AND CONCLUSIONS after reduced-intensity allogeneic transplantation for multiple-relapse
Ideally, there would be more prospective randomized aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27:426-432.
13. Sirvent A, Dhedin N, Michallet M, et al. Low nonrelapse mortality and
clinical trial data available to prove superior survival with prolonged long-term survival after reduced-intensity allogeneic stem
allo-HCT for FL, DLBCL, and MCL compared with alternative cell transplantation for relapsed or refractory diffuse large B cell lym-
approaches. No such studies have been successfully phoma: report of the Société Française de Greffe de Moelle et de
Thérapie Cellulaire. Biol Blood Marrow Transplant. 2010;16:78-85.
completed to date, however. One such study was attempted
14. Lazarus HM, Zhang MJ, Carreras J, et al. A comparison of HLA-identical
in FL, but was not completed because of poor accrual [85]. sibling allogeneic versus autologous transplantation for diffuse large B
Although it is true that a number of exciting targeted, bio- cell lymphoma: a report from the CIBMTR. Biol Blood Marrow Trans-
logical, and immunological therapies are emerging in NHL, plant. 2010;16:35-45.
15. van Kampen RJ, Canals C, Schouten HC, et al. Allogeneic stem-cell
how these new therapies might enhance or replace allo-HCT transplantation as salvage therapy for patients with diffuse large B-
is unclear. High-quality studies comparing novel agents with cell non-Hodgkin’s lymphoma relapsing after an autologous stem-cell
allo-HCT, or integrating such agents with allo-HCT, are transplantation: an analysis of the European Group for Blood and
Marrow Transplantation Registry. J Clin Oncol. 2011;29:1342-1348.
needed to answer such questions. In the meantime, based on 16. Rigacci L, Puccini B, Dodero A, et al. Allogeneic hematopoietic stem cell
the extensive literature currently available and summarized transplantation in patients with diffuse large B cell lymphoma relapsed
in this review, it is clear that for many patients with NHL, after autologous stem cell transplantation: a GITMO study. Ann Hem-
atol. 2012;91:931-939.
allo-HCT is the sole currently available therapy that offers 17. Bacher U, Klyuchnikov E, Le-Rademacher J, et al. Conditioning regi-
cure. mens for allotransplants for diffuse large B-cell lymphoma: myeloa-
Advances in the HCT field have enabled the successful blative or reduced intensity? Blood. 2012;120:4256-4262.
18. Hamadani M, Saber W, Ahn KW, et al. Impact of pretransplantation
application of this therapy in patients age >65 years. Access conditioning regimens on outcomes of allogeneic transplantation for
to allo-HCT in the United States historically has been quite chemotherapy-unresponsive diffuse large B cell lymphoma and grade
limited owing to a lack of insurance coverage. Despite this III follicular lymphoma. Biol Blood Marrow Transplant. 2013;19:
746-753.
limiation, there is now a body of evidence showing that pa-
19. Fenske TS, Ahn KW, Graff TM, et al. Allogeneic transplantation provides
tients with lymphoma in their 60s and 70s can in fact tolerate durable remission in a subset of DLBCL patients relapsing after autol-
and benefit from allo-HCT. Based on this evidence, we ogous transplantation. Br J Haematol. 2016;. http://dx.doi.org/10.1016/
strongly assert that allo-HCT now represents a standard of j.bbmt.2016.04.019 [Epub ahead of print].
20. Klyuchnikov E, Bacher U, Kroll T, et al. Allogeneic hematopoietic cell
care for older patients with NHL, and thus the associated transplantation for diffuse large B cell lymphoma: who, when and
costs should be covered by insurance carriers. how? Bone Marrow Transplant. 2014;49:1-7.
1550 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551

21. Bishop MR, Dean RM, Steinberg SM, et al. Clinical evidence of a graft- 42. Piñana JL, Martino R, Gayoso J, et al. Reduced-intensity conditioning
versus-lymphoma effect against relapsed diffuse large B-cell lym- HLA identical sibling donor allogeneic stem cell transplantation for
phoma after allogeneic hematopoietic stem-cell transplantation. Ann patients with follicular lymphoma: long-term follow-up from two
Oncol. 2008;19:1935-1940. prospective multicenter trials. Haematologica. 2010;95:1176-1182.
22. McClune BL, Ahn KW, Wang HL, et al. Allotransplantation for patients 43. Thomson KJ, Morris EC, Milligan D, et al. T-cell-depleted reduced-
age 40 years with non-Hodgkin lymphoma: encouraging intensity transplantation followed by donor leukocyte infusions to
progression-free survival. Biol Blood Marrow Transplant. 2014;20: promote graft-versus-lymphoma activity results in excellent long-term
960-968. survival in patients with multiply relapsed follicular lymphoma. J Clin
23. Kim JW, Kim SW, Tada K, et al. Allogeneic stem cell transplantation in Oncol. 2010;28:3695-3700.
patients with de novo diffuse large B-cell lymphoma who experienced 44. Khouri IF, Saliba RM, Erwin WD, et al. Nonmyeloablative allogeneic
relapse or progression after autologous stem cell transplantation: a transplantation with or without yttrium-90 ibritumomab tiuxetan is
Korea-Japan collaborative study. Ann Hematol. 2014;93:1345-1351. potentially curative for relapsed follicular lymphoma: 12-year results.
24. Vose JM, Bierman PJ, Anderson JR, et al. Progressive disease after high- Blood. 2012;119:6373-6378.
dose therapy and autologous transplantation for lymphoid malig- 45. Evens AM, Vanderplas A, LaCasce AS, et al. Stem cell transplantation for
nancy: clinical course and patient follow-up. Blood. 1992;80: follicular lymphoma relapsed/refractory after prior rituximab: a
2142-2148. comprehensive analysis from the NCCN lymphoma outcomes project.
25. Nagle SJ, Woo K, Schuster SJ, et al. Outcomes of patients with relapsed/ Cancer. 2013;119:3662-3671.
refractory diffuse large B-cell lymphoma with progression of lym- 46. Robinson SP, Canals C, Luang JJ, et al. The outcome of reduced-intensity
phoma after autologous stem cell transplantation in the rituximab era. allogeneic stem cell transplantation and autologous stem cell trans-
Am J Hematol. 2013;88:890-894. plantation when performed as a first transplant strategy in relapsed
26. Costa LJ, Micallef IN, Inwards DJ, et al. Time of relapse after initial follicular lymphoma: an analysis from the Lymphoma Working Party of
therapy significantly adds to the prognostic value of the IPI-R in pa- the EBMT. Bone Marrow Transplant. 2013;48:1409-1414.
tients with relapsed DLBCL undergoing autologous stem cell trans- 47. Klyuchnikov E, Bacher U, Kröger NM, et al. Reduced-intensity allog-
plantation. Bone Marrow Transplant. 2008;41:715-720. rafting as first transplantation approach in relapsed/refractory grades
27. Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma inter- one and two follicular lymphoma provides improved outcomes in
national prognostic index. Blood. 2004;104:1258-1265. long-term survivors. Biol Blood Marrow Transplant. 2015;21:
28. Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden 2091-2099.
follicular lymphomas between an initial no-treatment policy, pre- 48. Klyuchnikov E, Bacher U, Woo Ahn K, et al. Long-term survival out-
dnimustine, or interferon alfa: a randomized study from the Groupe comes of reduced-intensity allogeneic or autologous transplantation in
d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes relapsed grade 3 follicular lymphoma. Bone Marrow Transplant. 2016;
de l’Adulte. J Clin Oncol. 1997;15:1110-1117. 51:58-66.
29. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or 49. Yano S, Mori T, Kanda Y, et al. Favorable survival after allogeneic stem
re-treatment trial for low-tumor burden follicular lymphoma: Eastern cell transplantation with reduced-intensity conditioning regimens for
Cooperative Oncology Group protocol E4402. J Clin Oncol. 2014;32: relapsed/refractory follicular lymphoma. Bone Marrow Transplant.
3096-3102. 2015;50:1299-1305.
30. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rit- 50. Shea T, Johnson J, Westervelt P, et al. Reduced-intensity allogeneic
uximab versus CHOP plus rituximab as first-line treatment for patients transplantation provides high event-free and overall survival in pa-
with indolent and mantle-cell lymphomas: an open-label, multicentre, tients with advanced indolent B cell malignancies: CALGB 109901. Biol
randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203-1210. Blood Marrow Transplant. 2011;17:1395-1403.
31. Freedman A. Follicular lymphoma: 2014 update on diagnosis and 51. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with
management. Am J Hematol. 2014;89:429-436. allogeneic stem cell transplantation for relapsed follicular lymphoma
32. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular after nonmyeloablative conditioning with fludarabine, cyclophospha-
lymphoma after rituximab plus cyclophosphamide, doxorubicin, mide, and rituximab. Blood. 2008;111:5530-5536.
vincristine, and prednisone defines patients at high risk for death: 52. Lunning MA, Migliacci JC, Hilden P, et al. The potential benefit of
an analysis from the National LymphoCare Study. J Clin Oncol. 2015; allogeneic over autologous transplantation in patients with very early
33:2516-2522. relapsed and refractory follicular lymphoma with prior remission
33. Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative radio- duration of 12 months. Br J Haematol. 2016;173:260-264.
chemotherapy followed by autologous stem cell transplantation in first 53. Vose JM. Mantle cell lymphoma: 2015 update on diagnosis, risk-
remission prolongs progression-free survival in follicular lymphoma: stratification, and clinical management. Am J Hematol. 2015;90:
results of a prospective, randomized trial of the German Low-Grade 739-745.
Lymphoma Study Group. Blood. 2004;104:2667-2674. 54. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI)
34. Deconinck E, Foussard C, Milpied N, et al. High-dose therapy followed for patients with advanced-stage mantle cell lymphoma. Blood. 2008;
by autologous purged stem-cell transplantation and doxorubicin-based 111:558-565.
chemotherapy in patients with advanced follicular lymphoma: a ran- 55. Geisler CH, Kolstad A, Laurell A, et al. The Mantle Cell Lymphoma In-
domized multicenter study by GOELAMS. Blood. 2005;105:3817-3823. ternational Prognostic Index (MIPI) is superior to the International
35. Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with Prognostic Index (IPI) in predicting survival following intensive first-
interferon compared with CHOP followed by high-dose therapy with line immunochemotherapy and autologous stem cell transplantation
autologous stem cell transplantation in untreated patients with (ASCT). Blood. 2010;115:1530-1533.
advanced follicular lymphoma: the GELF-94 randomized study from 56. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rit-
the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 2006; uximab and cyclophosphamide, doxorubicin, vincristine, and predni-
108:2540-2544. sone significantly improves response and time to treatment failure, but
36. Ladetto M, De Marco F, Benedetti F, et al. Prospective, multicenter not long-term outcome in patients with previously untreated mantle
randomized GITMO/IIL trial comparing intensive (R-HDS) versus con- cell lymphoma: results of a prospective randomized trial of the
ventional (CHOP-R) chemoimmunotherapy in high-risk follicular German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;
lymphoma at diagnosis: the superior disease control of R-HDS does not 23:1984-1992.
translate into an overall survival advantage. Blood. 2008;111: 57. Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly
4004-4013. diagnosed mantle-cell lymphoma. N Engl J Med. 2015;372:944-953.
37. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves 58. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of
progression-free survival and survival in relapsed follicular non- bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of
Hodgkin’s lymphoma: results from the randomized European CUP trial. indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-2952.
J Clin Oncol. 2003;21:3918-3927. 59. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial
38. Sebban C, Brice P, Delarue R, et al. Impact of rituximab and/or high- treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:
dose therapy with autotransplant at time of relapse in patients with 1835-1844.
follicular lymphoma: a GELA study. J Clin Oncol. 2008;26:3614-3620. 60. Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense
39. Hamadani M. Reappraising the role of autologous transplantation for chemoimmunotherapy with rituximab-hyperCVAD alternating with
indolent B-cell lymphomas in the chemoimmunotherapy era: is it still rituximab-high dose methotrexate/cytarabine (R-MA) and without
relevant? Bone Marrow Transplant. 2013;48:1013-1021. stem cell transplantation in patients with untreated aggressive mantle
40. Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic he- cell lymphoma. Br J Haematol. 2010;150:200-208.
matopoietic cell transplantation in relapsed, refractory, and trans- 61. Merli F, Luminari S, Ilariucci F, et al. Rituximab plus hyperCVAD
formed indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26: alternating with high dose cytarabine and methotrexate for the initial
211-217. treatment of patients with mantle cell lymphoma, a multicentre trial
41. Hari P, Carreras J, Zhang MJ, et al. Allogeneic transplants in follicular from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012;156:
lymphoma: higher risk of disease progression after reduced-intensity 346-353.
compared to myeloablative conditioning. Biol Blood Marrow Trans- 62. Bernstein SH, Epner E, Unger JM, et al. A phase II multicenter trial of
plant. 2008;14:236-245. hyperCVAD MTX/Ara-C and rituximab in patients with previously
 T.S. Fenske et al. / Biol Blood Marrow Transplant 22 (2016) 1543e1551 1551

untreated mantle cell lymphoma; SWOG 0213. Annals of Oncology. predicts survival for patients with mantle-cell lymphoma receiving
2013;24:1587-1593. high-dose therapy and autologous stem-cell transplantation. J Clin
63. Kenkre VP, Long WL, Eickhoff JC, et al. Maintenance rituximab Oncol. 2011;29:3023-3029.
following induction chemoimmunotherapy for mantle cell lymphoma: 75. Vandenberghe E, Ruiz de Elvira C, Loberiza FR, et al. Outcome of
long-term follow-up of a pilot study from the Wisconsin Oncology autologous transplantation for mantle cell lymphoma: a study by
Network. Leuk Lymphoma. 2011;52:1675-1680. the European Blood and Bone Marrow Transplant and Autologous
64. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older Blood and Marrow Transplant Registries. Br J Haematol. 2003;120:
patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-531. 793-800.
65. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloa- 76. Cassaday RD, Guthrie KA, Budde EL, et al. Specific features identify
blative radiochemotherapy followed by autologous stem cell trans- patients with relapsed or refractory mantle cell lymphoma benefitting
plantation in first remission significantly prolongs progression-free from autologous hematopoietic cell transplantation. Biol Blood Marrow
survival in mantle-cell lymphoma: results of a prospective randomized Transplant. 2013;19:1403-1406.
trial of the European MCL Network. Blood. 2005;105:2677-2684. 77. Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell
66. Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six- transplantation after fludarabine and 2 Gy total body irradiation for
year follow-up after intensive immunochemotherapy for untreated relapsed and refractory mantle cell lymphoma. Blood. 2004;104:
mantle cell lymphoma followed by BEAM or BEAC þ autologous stem- 3535-3542.
cell support: still very long survival but late relapses do occur. Br J 78. Cook G, Smith GM, Kirkland K, et al. Outcome following reduced-
Haematol. 2012;158:355-362. intensity allogeneic stem cell transplantation (RIC alloSCT) for
67. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and relapsed and refractory mantle cell lymphoma (MCL): a study of the
autologous stem-cell transplantation for untreated patients with British Society for Blood and Marrow Transplantation. Biol Blood
mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27:6101-6108. Marrow Transplant. 2010;16:1419-1427.
68. Tam CS, Bassett R, Ledesma C, et al. Mature results of the M.D. 79. Le Gouill S, Kröger N, Dhedin N, et al. Reduced-intensity condi-
Anderson Cancer Center risk-adapted transplantation strategy in tioning allogeneic stem cell transplantation for relapsed/refractory
mantle cell lymphoma. Blood. 2009;113:4144-4152. mantle cell lymphoma: a multicenter experience. Ann Oncol. 2012;
69. Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab 23:2695-2703.
followed by autologous stem cell transplantation in mantle cell lym- 80. Hamadani M, Saber W, Ahn KW, et al. Allogeneic hematopoietic cell
phoma: a phase 2 study from the Groupe d’Etude des Lymphomes de transplantation for chemotherapy-unresponsive mantle cell lym-
l’Adulte. Blood. 2013;121:48-53. phoma: a cohort analysis from the Center for International Blood and
70. Hermine O, Hoster E, Walewski J, et al. Alternating courses of 3 CHOP Marrow Transplant Research. Biol Blood Marrow Transplant. 2013;19:
and 3 DHAP plus rituximab, followed by a high-dose ARA- 625-631.
Cecontaining myeloablative regimen and autologous stem cell trans- 81. Krüger WH, Hirt C, Basara N, et al. Allogeneic stem cell transplantation
plantation (ASCT) increases overall survival when compared to 6 for mantle cell lymphoma: final report from the prospective trials of
courses of CHOP plus rituximab followed by myeloablative radio- the East German Study Group Haematology/Oncology (OSHO). Ann
chemotherapy and ASCT in mantle cell lymphoma: final analysis of the Hematol. 2014;93:1587-1597.
MCL Younger Trial of the European Mantle Cell Lymphoma Network 82. Kanate AS, Mussetti A, Kharfan-Dabaja MA, et al. Reduced-intensity
(MCL net). ASH abstract. Blood. 2012;120(Suppl):151. transplantation for lymphomas using haploidentical related donors
71. Kolstad A, Laurell A, Jerkeman M, et al. Nordic MCL3 study: 90Y-ibri- versus HLA-matched unrelated donors. Blood. 2016;127:938-947.
tumomab-tiuxetan added to BEAM/C in non-CR patients before 83. Bachanova V, Burns LJ, Wang T, et al. Alternative donors extend
transplant in mantle cell lymphoma. Blood. 2014;123:2953-2959. transplantation for patients with lymphoma who lack an HLA matched
72. Fenske TS, Zhang MJ, Carreras J, et al. Autologous or reduced-intensity donor. Bone Marrow Transplant. 2015;50:197-203.
conditioning allogeneic hematopoietic cell transplantation for 84. Kasamon YL, Bolaños-Meade J, Prince GT, et al. Outcomes of non-
chemotherapy-sensitive mantle-cell lymphoma: analysis of trans- myeloablative HLA-haploidentical blood or marrow transplantation
plantation timing and modality. J Clin Oncol. 2014;32:273-281. with high-dose post-transplantation cyclophosphamide in older
73. Cowan AJ, Stevenson PA, Cassaday RD, et al. Pretransplantation mini- adults. J Clin Oncol. 2015;33:3152-3161.
mal residual disease predicts survival in patients with mantle 85. Tomblyn MR, Ewell M, Bredeson C, et al. Autologous versus reduced-
cell lymphoma undergoing autologous stem cell transplantation intensity allogeneic hematopoietic cell transplantation for patients
in complete remission. Biol Blood Marrow Transplant. 2016;22:380-385. with chemosensitive follicular non-Hodgkin lymphoma beyond first
74. Budde LE, Guthrie KA, Till BG, et al. Mantle cell lymphoma International complete response or first partial response. Biol Blood Marrow Trans-
Prognostic Index but not pretransplantation induction regimen plant. 2011;17:1051-1057.