B-CELL NHL, T-CELL NHL, AND HODGKIN LYMPHOMA (J ARMITAGE, SECTION EDITOR)

Allogeneic Stem Cell Transplantationfor Non-Hodgkin Lymphoma

Vijaya Raj Bhatt1

# Springer Science+Business Media New York 2016

Abstract Observational studies indicate a similar orhigher probability of disease control, higher risk of non-relapse mortality (NRM), and similar overall survival(OS) with allogeneic stem cell transplantation (alloSCT),compared to autologous SCT, in relapsed or refractorynon-Hodgkin lymphoma. Careful patient selection and uti-lization of reduced intensity conditioning (RIC) alloSCTmay allow reduction in NRM. The optimal conditioningregimen and the roles of radioimmunotherapy, T cell de-pletion, and tandem SCT continue to be explored. Recentstudies highlight comparable results with haploidenticalSCT and cord blood SCT, thus providing alternate donorsources. Disease relapse and late effects continue to bemajor problems. Optimization of SCT techniques (e.g.,improved graft-versus-host disease prophylaxis), post-transplant monitoring of minimal residual disease, andpost-transplant maintenance, or pre-emptive therapy(e.g., with novel therapies) are emerging strategies to re-duce the risk of relapse. Survivorship management using amultidisciplinary care approach, adoption of healthy life-style, and socioeconomic counseling are integral parts of ahigh-quality transplant program.

Keywords Non-Hodgkin lymphoma . Diffuse large B celllymphoma . Follicular lymphoma .Mantle cell lymphoma .

Peripheral Tcell lymphoma . Autologous stem celltransplantation . Allogeneic stem cell transplantation

Introduction

Non-Hodgkin lymphoma (NHL) is a significant public healthproblem and will account for an estimated 20,000 deaths in2016 [1]. Improvement in upfront immunochemotherapy andsalvage therapy in recent years has resulted in prolonged dis-ease control or cure in up to two thirds of patients [1].However, the remaining one third of patients, particularlythose with high-risk NHL, may succumb to refractory or re-lapsed disease or non-relapse mortality (NRM) [2–7]. A judi-cious use of hematopoietic stem cell transplantation (SCT) inselect patients can reduce deaths related to NHL. The use ofautologous SCT (autoSCT) in refractory or relapsedNHL is associated with improved overall survival (OS)and can result in prolonged disease control or cure intransplant-eligible patients. Conversely, upfront consoli-dation autoSCT following achievement of first completeor partial remission in high-risk aggressive NHL, mantlecell lymphoma, and peripheral T cell lymphoma mayprolong progression-free survival without OS advantage(reviewed in Bhatt and Vose [3]). Allogeneic SCT(alloSCT) is generally reserved for young and fit pa-tients with refractory or heavily pre-treated disease oras a salvage therapy after the failure of autoSCT [3].In this article, I will discuss the role of alloSCT inNHL, compare different intensities of conditioning, andreview some of the possible strategies to improve out-comes of patients undergoing alloSCT.

This article is part of the Topical Collection on B-cell NHL, T-cell NHL,and Hodgkin Lymphoma

* Vijaya Raj Bhattvijaya.bhatt@unmc.edu

1 Department of Internal Medicine, Division ofHematology-Oncology, University of Nebraska Medical Center,987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA

Curr Hematol Malig RepDOI 10.1007/s11899-016-0319-0

Selection of the Type of Transplant

A randomized trial comparing the outcomes of autoSCT andmyeloablative alloSCT in NHL is lacking and unlikely to beperformed in foreseeable future. However, a number of obser-vational studies have compared the outcomes of autoSCT andalloSCT (Table 1) [8–11]. Inherent to retrospective compari-sons, significant differences exist between the two groupssuch as age of the patients, disease risk, and conditioningregimens. Generally, myeloablative alloSCT group is fre-quently younger but has higher-risk disease (e.g., higher inter-national prognostic index or chemorefractory disease) thanautoSCT group. Age, chemosensitive disease, number of priorchemotherapy regimens, and disease status at SCT can affectsurvival [3, 8]. Hence, such differences in two groupsmay limitdefinite conclusion. Additionally, conditioning regimens andgraft-versus-host disease (GVHD) prophylaxis are variable.BEAM (carmustine, etoposide, cytarabine, and melphalan) andBEAC (carmustine, cytarabine, etoposide, and cyclophospha-mide) are commonly used conditioning regimens for autoSCT,whereas the use of total body irradiation (TBI)-based condition-ing is variable [8]. Busulfan/cyclophosphamide andcyclophosphamide/TBI are commonly used conditioning regi-mens for alloSCT. Most of the comparative studies provide sur-vival data at 5 years or less, so differences in long-termoutcomesremain unclear. Further, the outcomes of alloSCT and autoSCTcontinue to improve; hence, the differences may change withadvances in transplant techniques.Within such limitations, priorstudies largely indicate that alloSCThas a similar or higher prob-abilityofdiseasecontrolandahigher riskofNRM,thusachievingOS similar to or lower than autoSCT [3, 8–11, 14].

In autoSCT, disease relapse remains to be the most com-mon cause of deaths [15]; hence, therapy with higher curativepotential is desired. Although myeloablative alloSCT is con-sidered by many transplant physicians to have higherBcurative^ potential than autoSCT, the high risk of NRMand lack of randomized comparison with autoSCT haveprohibited the confirmation of differences in curative poten-tial. In alloSCT, disease relapse and NRM are importantcauses of deaths. Thus, patient selection and individualizedmanagement plan may allow us to make the best use of avail-able SCT approaches. The key factors that determine thechoice of SCT are the age, performance status and comorbid-ities of the patients, disease status, response to prior therapies,matched donor availability, and institutional guidelines(Fig. 1). Hematopoietic cell transplantation comorbidity indexis predictive of NRM and survival in alloSCT recipients [16]as well as in lymphoma patients undergoing autoSCT [17].Both younger and older patients, who have indolent NHL orhave had a prolonged duration of first remission and are ableto achieve a second remission after two to three cycles ofsalvage chemotherapy, may achieve prolonged disease controlwith high-dose conditioning regimen and autoSCT. The use of

alloSCT in such patients may subject them to an unnecessaryhigh risk of NRM and should generally be avoided. In youngpatients with aggressive disease and poor/suboptimal re-sponse to prior therapies, who have Karnofsky performancestatus of ≥80 %, low transplant comorbidity index, and 8/8matched related or unrelated donor, myeloablative alloSCTmay be the better SCT strategy. AlloSCT may offer a higherchance for long-term disease control in such patients and maybe preferred. Patients at high risk of NRM and disease relapsemay preferably be enrolled in clinical trials of novel therapies.

Conditioning Regimen in AlloSCT

Intensity of Conditioning Regimen

Patients >60 years are frequently not considered a good can-didate for myeloablative alloSCT but may be eligible for re-duced intensity conditioning (RIC) or non-myeloablative(NMA) alloSCT. RIC/NMA alloSCT may also be an optionfor patients with poor performance status, coexisting comor-bidities, and high transplant comorbidity index or patientsrelapsing after prior autoSCT or alloSCT. Consequently,RIC/NMA alloSCT has been increasingly utilized and cur-rently accounts for up to three quarters of alloSCT [18].Recently, a number of studies have demonstrated that geriatricassessment can uncover previously undocumented impair-ments in functional status and frailty [19, 20]; hence, it maybe utilized to better determine eligibility, risk of NRM, and OSwith alloSCT [21]. Better risk stratification can also guideselection of the intensity of conditioning regimen.

The outcomes of RIC/NMA conditioning have not beencompared to myeloablative alloSCT in a randomized trial.RIC/NMA alloSCT is frequently used in older and less-fitpatients; hence, retrospective comparisons between RIC/NMA and myeloablative alloSCT have limitations. Withinsuch limitations, the risk of NRM appears to be somewhatlower for RIC/NMA alloSCT; however, the risk of acute andchronic GVHD is similar to myeloablative alloSCT. Both OSand progression-free survival (PFS) appear to be largely sim-ilar between the two groups (Table 2) [18, 22, 23•, 24•, 25].

In recent years, the use of RIC/NMA alloSCT has resultedin a low risk of NRM, even in older patients [26, 27]. Inyounger and fit patients, RIC/NMA alloSCT is expected tohave a significantly lower NRM. Hence, the use of RIC/NMA alloSCT may allow a potentially curative SCT strategywith relatively lower NRM, as compared to autoSCT.Retrospective comparisons between autoSCT and RIC/NMAalloSCT do not support this notion; however, this is likely dueto differences in patients’ characteristics (Table 1) [11, 12,13•]. Indeed, a randomized Blood and Marrow TransplantClinical Trials Network (BMT CTN) trial of relapsed,chemotherapy-sensitive follicular lymphoma demonstrated

Curr Hematol Malig Rep

Tab

le1

Com

parisonof

allogeneicandautologous

stem

celltransplant

inrelapsed

orrefractory

non-Hodgkin

lymphom

a

Author,year

NCom

parison

Com

mon

conditioning

regimens

NRM

AcuteGVHD

Chronic

GVHD

PFS/DFS

OS

Lazarus,2010[8]

916DLBCL

AutoS

CTvs.M

AMRD

alloSC

TBEAM

andothersvs.

Cy/TBIor

Bu/Cy

12vs.41%

at1year

42%,grade

II–IV

23%

at1year

43vs.22%

at5years

49vs.22%

at5years

vanBesien,2003

[9]a

904FL

Purged

autoSC

Tvs.

unpurged

autoSC

Tvs.

MAMRDalloSCT

TBI34

vs.31vs.68

%8vs.4

vs.24%

at1year

37%,grade

II–IV

24%

39vs.31vs.45%

at5years

62vs.55vs.51%

at5years

Ganti,

2005

[10]

97MCL

AutoS

CTvs.M

AMRD

alloSC

TBEAM

+/−rituximab

orBEACvs.C

y/TBI

0vs.19%

at100days,

p<0.01

NA

NA

39vs.44%at5years,p=0.85

47vs.49%

at5years,

p=0.51

Smith

,2013[11]

241TcellNHL

AutoS

CTvs.M

Avs.

NMA/RIC

alloSCT

BEAM

orTBIvs.

various

7vs.29vs.27%

at1year,p

<0.001

NA

NA

47vs.36vs.33%

at3years,

p<0.18

59vs.39vs.52%

at3years,p<0.03

Tomblyn,2011[12]

b30

FL

AutoS

CTvs.R

ICalloSCT

CBVor

Cy/TBIand

etoposidevs.F

lu/Cy/

rituximab

15vs.0

%at1year

NogradeII–IV

50%

63vs.86%

at3years

73vs.100

%at3years

Fenske,2014[13•]

519MCL

AutoS

CTvs.R

ICalloSC

TBEAM

orTBIbasedvs.

Flu/Mel,F

lu/Bu,TBI

2Gy,Flu/Cy

3vs.25%

at1year,

p<0.001c

NA

NA

52vs.55%

at5years,

p=0.74

c61

vs.62%

at5years,

p=0.95

c

Allo

SCTallogeneicstem

celltransplantation;autoSC

Tautologous

stem

celltransplantation;BEACcarm

ustin

e,cytarabine,etoposide,and

cyclophosphamide;BEAM

carm

ustin

e,etoposide,cytarabine,and

melphalan;Bubusulfan;CBVcyclophosphamide,carm

ustin

e,andetoposide;

Cycyclophosphamide;

DFSdisease-free

survival;DLBCLdiffuselargeBcelllymphom

a;FLfollicularlymphom

a;Flu

fludarabine;GVHDgraft-versus-hostdisease;M

Amyeloablativ

econditioning;MCLmantle

celllymphom

a;Melmelphalan;M

RDmatched

relateddonor;Nnumber;NAnotavailable;NHLnon-Hodgkin

lymphom

a;NMAnon-myeloablativ

econditioning;

NRM

non-relapsemortality;

OSoverallsurvival;PFSprogression-free

survival;R

ICreducedintensity

conditioning;

TBItotalb

odyirradiation

aOlder

studywith

transplant

performed

inpre-rituximab

era(1990–1999);however,thisisthelargestcom

parisonof

autoSC

TandalloSC

Tin

follicularlymphom

abProspectiv

etrialclosedearlybecauseof

slow

accrual

cResultsareforearlycohorts(patientstransplanted

infirstpartialorcom

pleteremission

follo

wingtheuseof

oneor

twopriorchemotherapy

regimens).T

hedifferencesintheoutcom

esof

twogroups

were

similarin

latetransplantationcohorts

Curr Hematol Malig Rep

the possibility of improved outcomes with RIC alloSCT overautoSCT. In this study, the use of RIC alloSCT usingfludarabine, cyclophosphamide, and rituximab, compared toautoSCT, resulted in a more favorable NRM (0 vs. 15 % at1 year), PFS (86 vs. 63 % at 3 years), and OS (100 vs. 73 % at3 years). Unfortunately, slow accrual resulted in prematureclosure of the study, and only 30 patients could be enrolled.Also, the NRM associated with autoSCT was unusually high[12] and not observed any more at our institution.

Specific Conditioning Regimen

The optimal conditioning regimen with alloSCT for NHL hasnot been tested in a randomized trial. Although the risk oflong-term toxicities of TBI-based conditioning including sec-ondary malignancies, pulmonary toxicities, infertility, and cat-aract formation [28–30] makes TBI less preferred, the optimalconditioning regimen is not established. Retrospective studies

demonstrate that busulfan/cyclophosphamide andcyclophosphamide/TBI are frequently used myeloablativeregimens for alloSCT. Fludarabine/melphalan, fludarabine/low-dose busulfan, fludarabine/cyclophosphamide, and low-dose TBI with or without fludarabine are the most commonRIC/NMA conditioning regimens [18, 22, 23•, 24•, 25](Table 2).

Older studies comparing cyclophosphamide/TBI tobusulfan/cyclophosphamide utilized oral busulfan withoutany dose adjustment. An International Bone MarrowTransplant Registry retrospective study in AML demonstratedthat the use of cyclophosphamide/TBI, compared to busulfan/cyclophosphamide, resulted in a lower risk of sinusoidal ob-struction syndrome (SOS) and relapse risk, particularly CNSrelapse; however, other outcomes including NRM, leukemia-free survival, and OS were comparable [31]. A higher inci-dence of SOS was confirmed by a meta-analysis of five ran-domized studies also [32]. While high level of busulfan is

Relapsed or refractory non-Hodgkin lymphoma

Salvage chemoimmunotherapy

Stable or progressive disease, Adult patients >70-75 years, KPS <70%, and/or High HCT CI >2

Complete or partial remission, Adult patients <70-75 years, KPS >70-80%, and Low HCT CI Index 0-1

Clinical trial of novel therapies (preferred) SCT on select patients Palliative therapy Best supportive care Hospice

Indolent disease Prolonged duration of first remission

Aggressive disease Short duration of remission or multiply relapsed Marrow involvement Matched donor available

High-dose chemotherapy/autoSCT*

AlloSCT* -MA if <50-60 years -NMA/RIC if >50-60 years Failure or relapse

MRD monitoring Post-SCT maintenance Pre-emptive treatment DLI Novel therapies (all strategies preferably performed in a context of a trial)

Fig. 1 Algorithm formanagement of relapsed/refractory non-Hodgkinlymphoma. In general, clinicaltrials are preferred for mostpatients with relapsed/refractorynon-Hodgkin lymphoma. *Trialsneeded to determine optimalconditioning regimen forautoSCT and alloSCT, butchemotherapy-alone conditioningregimen may generally bepreferred over total bodyirradiation-based conditioningregimen. AlloSCT allogeneic stemcell transplantation, autoSCTautologous stem celltransplantation, DLI donorlymphocyte infusion, HCT CIhematopoietic cell transplantcomorbidity index, KPSKarnofsky performance status,MA myeloablative conditioning,MRD minimal residual disease,NMA non-myeloablativeconditioning, RIC reducedintensity conditioning, SCT stemcell transplantation

Curr Hematol Malig Rep

associated with an increased risk of SOS, low level is associ-ated with increased risk of graft rejection and, possibly, dis-ease relapse [28]. In recent years, dose-adjusted IV busulfan isused, which may improve outcomes. More recent studiescomparing the outcomes of cyclophosphamide/TBI and IVbusulfan/cyclophosphamide indeed demonstrate at least simi-lar PFS and OS with busulfan/cyclophosphamide, with sug-gestions of possibly lower risk of GVHD and NRM, higherrisk of SOS, varying risk of relapse, and improved PFS/OS insome but not other studies [33–35].

In a randomized trial, busulfan/fludarabine, compared tobusulfan/cyclophosphamide, resulted in lower risk of grade3 or higher infection and gastrointestinal adverse events, sim-ilar NRM, and lower event-free survival and OS. Busulfan/fludarabine group had somewhat of a higher percentage ofALL patients and mismatched transplant [36]. In another ran-domized trial of AML in first remission, busulfan/fludarabine,compared to busulfan/cyclophosphamide, resulted in lowerrisk of regimen-related toxicities and similar risk of relapse,PFS, and OS [37]. A recent phase III trial in AML patientsbetween the age of 40–65 years demonstrated lower risk ofNRM (8 vs. 15 % at 1 year) and similar risk of relapse, PFS,and OS with busulfan/fludarabine, compared to busulfan/cyclophosphamide [38]. Taken together, these studies indicatethat busulfan/fludarabine may be associated with lower risk ofcomplications and NRM than busulfan/cyclophosphamide ingeneral; however, these studies had very few patients withNHL. Hence, conclusion regarding efficacy in NHL cannotbe drawn.

Radioimmunotherapy

Radioimmunotherapy such as 131I-tositumomab or 90Y-ibritumomab tiuxetan has demonstrated anti-lymphoma activ-ity when utilized as monotherapy or as a part of conditioningregimen before autoSCT in NHL [39–42]. The feasibility ofutilizing radioimmunotherapy as a part of RIC alloSCT hasbeen demonstrated in NHL; the outcomes are promising[43–46]. However, their role compared to other conditioningregimen is unclear. This is particularly important given the factthat despite promising results in earlier studies in relapsedNHL [47–49], a large BMT CTN phase III trial demonstratedno improvement in OS in relapsed diffuse large B cell lym-phoma with the addition of 131I-tositumomab to BEAM priorto autoSCT [50].

T Cell Depletion

T cells play an important role in graft-versus-lymphoma ef-fect, engraftment, and immune reconstitution; however, Tcells are also critical players in the causation of GVHD [51].GVHD can contribute to NRM, morbidity, and poor quality oflife. The approach to Tcell depletion, achieved with the use ofT

able2

Com

parisonof

myeloablativ

eandreducedintensity

allogeneicstem

celltransplant

innon-Hodgkin

lymphom

a

Author,year

NCom

parison

Com

mon

conditioning

regimens

NRM

AcuteGVHD

ChronicGVHD

PFS/DFS

OS

Bacher,

2012

[22]

396DLBCL

MAvs.R

ICvs.

NMA

Cy/TBIor

Bu/Cyvs.F

lu/M

elor

Bu/Fluvs.T

BIor

Flu/Cy

56vs.47vs.36%

at5years,p=0.007

43vs.43vs.44%,grade

II–IV,p

=0.9

35vs.39vs.33%

at1year,p

=0.6

18vs.15vs.25%

at5years,p=0.3

18vs.20vs.26%

at5years,p=0.3

Hari,2008

[18]

208FL

MAvs.R

ICCy/TBIor

Bu/Cyvs.F

lu/M

el,

Bu/Fluor

Flu/Cy

23vs.23%

at1year,

p=0.9

36vs.42%,grade

II–IV

(p=.026)

44vs.58%

at1year,

p=0.06

67vs.55%

at3years,

p=0.07

71vs.62%

at3years,

p=0.15

Ham

adani,2013

[23•]

202refractory

MCL

MAvs.R

IC/NMA

Bu/Cyor

Cy/TBIvs.F

lu/M

elor

Bu/Fluor

TBIor

Flu/TBIor

Flu/Cy

43vs.38%

at1year,

p=0.56

36vs.37%,grade

II–IV

(p=0.93)

35vs.43%

at1year,

p=0.34

20vs.25%

at3years,

p=0.53

25vs.30%

at3years,

p=0.45

Ham

adani,

2013

[24•]

533refractory

DLBCL/

gradeIIIFL

MAvs.R

IC/NMA

Bu/Cyor

Cy/TBIvs.F

lu/M

elor

Bu/Fluor

TBIor

Flu/TBIor

Flu/Cy

47vs.36%

at1year,

p=0.017

29vs.31%,grade

II–IV

(p=0.68)

33vs.38%

at1year,

p=0.27

19vs.23%

at3years,

p=0.40

19vs.28%

at3years,

p=0.02

Rodriguez,

2006

[25]

88NHL

MAvs.R

ICCy/TBIor

Bu/Cyvs.

Flu/Mel

33vs.28%

at1year,

p=0.40

45vs.65%,grade

II–IV

72vs.76%

46vs.40%

at2years,

p=0.46

52vs.53%

at2years,

p=0.99

Allo

SCTallogeneicstem

celltransplantation,Bubusulfan,C

ycyclophosphamide,DFSdisease-free

survival,D

LBCLdiffuselargeBcelllymphom

a,FLfollicularlym

phom

a,Flufludarabine,GVHDgraft-

versus-hostdisease,MAmyeloablativ

econditioning,

MCLmantle

celllymphom

a,Melmelphalan,Nnumber,NHLnon-Hodgkin

lymphom

a,NMAnon-myeloablativ

econditioning,

NRM

non-relapse

mortality,OSoverallsurvival,PFSprogression-free

survival,R

ICreducedintensity

conditioning,TBItotalb

odyirradiation

Curr Hematol Malig Rep

alemtuzumab or anti-thymocyte globulin, has been investigat-ed to determine its impact on GVHD and NRM. However,these studies have not demonstrated a reduction in NRM orimprovement in OSwith Tcell-depleted RIC alloSCT [52, 53]despite an improvement in the risk of acute and chronicGVHD [52]. This is because of increased risk of infectionsand relapse likely consequent to decline in immune reconsti-tution and graft-versus-lymphoma effect [52]. A study of re-lapsed follicular lymphoma (N=126) utilized BEAM condi-tioning for both T cell-depleted alloSCT and autoSCT; T celldepletion was achieved with the use of alemtuzumab. T cell-depleted alloSCT resulted in a higher 1-year NRM (20 vs.2 %, p= .001), a lower 3-year relapse (20 vs. 43 %, p= .01),and similar 3-year DFS (58 vs. 56 %, p= .90) and OS (69 vs.67 %, p= .99) as autoSCT [54]. Until well-designed strategiesto reduce post-transplant relapse and infections are available,the role of T cell-depleted RIC alloSCT is limited. T cell-depleted alloSCTs are unlikely to be a good strategy in pa-tients with active disease at transplant or those with aggressivedisease; however, it may possibly have a role in patients withprior graft failure and those with GVHD who are undergoingsecond alloSCT for relapsed NHL.

In the above studies of T cell-depleted alloSCT in follicularlymphoma, the use of donor lymphocyte infusion (DLI)(starting dose of 1×106/kg) in patients with mixed chimerismachieved full donor chimerism. DLI also resulted in a signif-icant decline in the relapse rate and remission in relapses afteralloSCT [52–54]. The graft-versus-lymphoma effect of DLIcan take several weeks to manifest, so DLI may not be aseffective in patients with aggressive NHL or those patientsprogressing within a few months of alloSCT. The potentialrisks of DLI include GVHD and bone marrow aplasia. Therisk of GVHD precludes the use of DLI in patients with activeGVHD [53], but not in patients with a prior history of GVHD.

AlloSCTAfter AutoSCT Failure

Patients who have disease progression following the use ofautoSCT generally have a poor prognosis. If such patients arefit and can undergo alloSCT, a proportion of patients mayachieve durable disease control, particularly those patients,who have good performance status, prolonged remission dura-tion with autoSCT, and disease remission at the time of alloSCT[55]. Many patients, who fail autoSCT, are older or less-fit andmay only be candidates for RIC alloSCT. Conversely, otherpatients may be able to undergo myeloablative alloSCT. In aEuropean Bone Marrow Transplantation Registry (EBMTR),patients with diffuse large B cell lymphoma relapsing afterautoSCT underwent myeloablative alloSCT (n=37) or RICalloSCT (n=64). This resulted in NRM of 28 %, relapse rateof 30 %, PFS of 41 %, and OS of 53 % at 3 years. Patients whorelapsed within 12 months of autoSCT had higher NRM and

lower PFS [56]. Another study utilized total lymphoid irradia-tion and anti-thymocyte globulin conditioning prior to alloSCTin 47 lymphoma (32 NHL) patients relapsing after autoSCT.This strategy resulted in 3-year OS, PFS, and NRM of 81, 44,and 7 %. More than half of patients (n=25) had disease relapsewithin a median of less than a year after alloSCT; 44 % ofpatients with relapses post-alloSCT achieved durable remissionwith the use of DLI or chemoradiotherapy [57].

Tandem AutoSCT and RIC/NMA AlloSCT

Tandem autoSCT and RIC/NMA alloSCT is performed with agoal to secure advantages of both autoSCT (prolongs OS with alow NRM) and alloSCT (graft-versus-lymphoma effect resultingin high curative potential) without a risk of high NRMassociatedwithmyeloablative alloSCT. In a study of relapsed follicular lym-phoma (n=27), the use of tandem autoSCT and NMA alloSCTresulted in NRM of 4 % at 3 years and PFS and OS of 96 % at3 years [58]. In another study of high-risk lymphoma (n=42)(relapsed/refractory disease or high-risk histology), 29 patientswere able to undergo tandem autoSCT and RIC alloSCT. Thiswas associated with a NRM of 11 %, PFS of 72 %, and OS of89% at 2 years. Patients, who underwent tandemSCT, had betterPFS and OS at 2 years, compared to patients who could onlyundergo autoSCT. Additionally, none of the nine patients withdiffuse large B cell lymphoma with concurrent over-expressionof BCL-2 and MYC proteins (including two patients whounderwent autoSCT only) experienced relapse. However, selec-tion bias confounds the result as patientswith disease progressionafter autoSCT did not proceed to alloSCT [59•]. Overall, tandemSCTisapromisingapproach,whichshouldbe investigatedfurtherin prospective trials.

Haploidentical and Cord Blood SCT

Donor availability is an important issue, particularly in patientsfrom ethnicminorities. The use of haploidentical donor and cordblood allows alloSCT in the vast majority of transplant eligiblepatients. Additionally, timely availability of donor may expeditealloSCT, whichmay be particularly valuable in patients with ag-gressive NHL. Early alloSCT, once remission is achieved, mayavoidchemotherapy-related toxicitiesandhencehasapotential toreduceNRM.The results of haploidentical transplant using post-transplantcyclophosphamidearecomparable tomatchedunrelat-ed donor alloSCT [60–62]. Umbilical cord blood alloSCT [63]has also shown promising results in hematologic malignancies;however, delayed engraftment and risk of infections continue tobeaproblem.Aretrospectivestudyindicated that theoutcomesofhaploidentical donor alloSCT may be better than cord bloodalloSCT [64]. However, the result of BMT CTN 1101 trial thatcompares the two strategies is awaited.

Curr Hematol Malig Rep

Strategy to Optimize Outcomes of AlloSCT

AlloSCT techniques, GVHD prophylaxis, supportive care, andmedical management continue to improve; such advancementshave reducedNRMand improvedOSdespite the use of alloSCTin older patients in recent years [65]. Transplant techniques canfurther be individualized with a goal to optimize outcomes. Forexample, the use of bonemarrow grafts may decrease the risk ofchronic GVHD and long-term toxicities from chronic GVHD[66],whichmaybeparticularly important forpatientsundergoingmismatched unrelated alloSCT. More recently, the use of post-transplant high-dose cyclophosphamide as GVHD prophylaxis[67, 68] and higher CD8+Tcell dosewith RIC alloSCT [69] hasbeen shown to potentially reduce TRM and chronic GVHD andimprove OS. Use of such techniques to lower TRM may allowpotentially curative alloSCT in less-fit patients and earlier in thedisease course.

The timing of SCT may influence the outcomes. The sur-vival in NHL is better with the use of autoSCT earlier in thedisease course [70, 71]. Therefore, autoSCT is frequently rec-ommended in second remission for many types of NHL, ratherthan later in the disease course. In mantle cell lymphoma andperipheral T cell lymphoma, outcomes may be better withautoSCT in first remission than subsequently in the diseasecourse [13•, 72]. Multiple prior therapies also predict for poorsurvival in patients treated with alloSCT [9, 11, 13•, 73] Forexample, the CIBMTR study in mantle cell lymphoma demon-strated a superior 5-year OS for early versus late RIC alloSCT(62 vs. 31 %, p=0.005) [13•]. Although autoSCT or alloSCTmay salvage some patients with refractory NHL, the outcomesof SCT are better in patients with chemosensitive disease andthose with disease in remission at the time of SCT [3]. Pooroutcomes associated with heavily pre-treated disease may, thus,be reflective of chemorefractoriness of the disease or cumula-tive damage of prior therapies and declining body reserve.Nonetheless, if SCT is to be offered, it should be offered earlierin the disease course.

Lastly, the utilization of SCT is currently low; hence, eligi-ble patients should be referred for potential SCT to transplantcenters. Such referral should be timely to avoid delays in SCT,which may increase deaths while awaiting for SCT. This isparticularly important in aggressive B cell NHL and peripher-al T cell lymphoma [74].

Post-Transplantation Monitoring

In NHL, disease monitoring after SCT generally includes his-tory and physical examination, complete blood count, bloodchemistry, and serum LDH. Most of the lymphoma relapsesare detected based on history and physical examination;hence, routine surveillance scans are not recommended [3].Although OS with the use of autoSCT and alloSCT has

improved in recent years [15, 65] and the risk of infection-related deaths has decreased [15], the risk of disease relapseremains high and is the most important cause of deaths afterSCT. In the post-alloSCT setting, disease status and potentialrisk of relapse are identified by disease restaging at about3 months; monitoring of donor chimerism in RIC/NMAalloSCT; and assessment of minimal residual disease (MRD)by flow cytometry, cytogenetics, and molecular markers [75,76]. Early tapering of immunosuppression after RIC alloSCTmay allow graft-versus-lymphoma effect to emerge in patientsat high risk of relapse such as declining donor chimerism,although possibly at an increased risk of GVHD. Post-transplant maintenance therapy, MRD monitoring, and pre-emptive therapy for MRD are increasingly being explored toreduce risk of clinical relapse. In autoSCT, detection of MRDafter SCT predicts a higher risk of subsequent clinical relapse[75, 76] and hence allows pre-emptive therapy to successfullydelay clinical relapse [75, 77]. Despite an achievement ofmolecular remission and prolongation in PFS, this strategyhas not yet been shown to improve OS [76–78]. Althoughnot well studied, post-transplant maintenance with tyrosinekinase inhibitors in chronic myeloid leukemia andPhiladelphia chromosome-positive acute lymphoid leukemiais a routine practice in many institutions. Recent promisingresults of post-transplant maintenance with sorafenib in acutemyeloid leukemia have generated great excitement among thetransplant physicians [79, 80]. However, the use of post-alloSCT rituximab in relapsed or refractory NHL failed toimprove OS or the risk of GVHD in a phase II trial [81•].Half of the patients in rituximab group had received rituximabpreviously; hence, it can be argued that rituximab was not anoptimal maintenance drug in that setting. The use of noveltherapies, which has not been previously utilized in aparticular patient, may be a better maintenance drug.For example, the use of brentuximab vedotin inHodgkin lymphoma after alloSCT has shown to lowerrelapse rate and improve PFS [82].

Impact of Novel Therapies

Understanding of the lymphoma biology at the molecular lev-el has rapidly advanced drug development in recent years.Several novel targeted therapies and immunotherapies suchas ibrutinib [83], obinutuzumab [84], idelalisib [85], ABT-199 [86], antibody-drug conjugate such as polatuzumabvedotin (anti-CD79b antibody-drug conjugate) [87],lenalidomide [88], immune checkpoint inhibitors [89], andanti-CD19 chimeric antigen receptor (CAR) T cells [90] havedemonstrated anti-lymphoma activity. Some of these agentshave been approved for therapy and integrated in therapeuticarmamentarium for NHL. The availability of such therapieshas important implications for management of NHL and the

Curr Hematol Malig Rep

use of SCT. First, the availability of efficacious therapies thatcan induce remission in a large proportion of relapsed NHLraises the question of optimal timing of SCT.Many physiciansand patients may decide to delay the use of SCT in preferencefor novel therapies within or outside of a clinical trial. Second,these agents can be utilized to achieve a high-quality remis-sion before SCT in relapsed NHL. Compared to salvage che-motherapy, these agents may allow remission with relativepreservation of patient’s performance status. Third, these nov-el therapies may offer safe and effective agent for incorpora-tion into conditioning regimen, post-transplant consolidation/maintenance, and pre-emptive therapy. Finally, these noveltherapies can be used alone or with DLI in the managementof relapses after alloSCT. These are some of the potential areasfor future research.

Survivorship Issues

Patients, who have undergone an alloSCT, are at a risk ofacute and chronic GVHD, opportunistic infection, secondarysolid malignancies, and other long-term toxicities of priortherapies which include cardiac, pulmonary, endocrine, andrenal sequelae; sexual dysfunction; poor quality of life; andfinancial toxicities [91, 92]. Importantly, long-term survivorsare at a higher risk of mortality because of such late effects[93]. Optimal management of transplant survivors requires adedicated multidisciplinary team experienced and interestedin survivorship issues, development of individualized compre-hensive survivorship plan, coordination of care with primarycare providers, and patient engagement [94]. Digital technol-ogy, frequently used by millennial generation in particular,may be integrated in oncologic care to facilitate survivorshipmanagement, e.g., use of mobile device for assessing risk oftoxicities, telemonitoring of symptoms, patient education, andreminders to enhance adherence to medical advice. Provisionof good survivorship plan and socioeconomic counseling mayimprove longevity and quality of life of transplant recipients.

Conclusion

Advances in the management of NHL have resulted in a sig-nificant improvement in OS in last few decades [1]. Relapsedor refractory NHL, however, continues to have poor out-comes. Although significant improvement has been made inthe field, a paucity of randomized trials in alloSCT limits ourcurrent understanding of optimal transplant strategy. The uti-lization of novel therapies, optimization of conditioning regi-men, improvement in SCT techniques, post-transplant diseasemonitoring, and maintenance strategy have potential to im-prove outcomes of relapsed or refractory NHL and are impor-tant areas of ongoing research. The use of haploidentical

[60–62] or cord blood donor [63] demonstrates results com-parable to matched unrelated donor alloSCT. Such alternatedonor option also allows timely access to alloSCT. GVHDand late effects are important consequences of alloSCT.Hence, provision of multidisciplinary team specializing inGVHD management and survivorship issues can immenselyenhance overall health and quality of life of transplant survi-vors [94].

Acknowledgments This work was supported by the University ofNebraska Medical Center, College of Medicine, Physician-ScientistTraining Program Grant 2015–2016.

Compliance with Ethical Standards

Conflict of Interest The author declares that he has no conflicts ofinterest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA CancerJ Clin. 2016;66(1):7–30.

2. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P,et al. The revised International Prognostic Index (R-IPI) is a betterpredictor of outcome than the standard IPI for patients with diffuselarge B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857–61.

3. Bhatt VR, Vose JM. Hematopoietic stem cell transplantation fornon-Hodgkin lymphoma. Hematol Oncol Clin North Am.2014;28(6):1073–95.

4. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L,et al. R-CVP versus R-CHOP versus R-FM for the initial treatmentof patients with advanced-stage follicular lymphoma: results of theFOLL05 trial conducted by the Fondazione Italiana Linfomi. J ClinOncol. 2013;31(12):1506–13.

5. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E,Schmits R, et al. Frontline therapy with rituximab added to thecombination of cyclophosphamide, doxorubicin, vincristine, andprednisone (CHOP) significantly improves the outcome for patientswith advanced-stage follicular lymphoma compared with therapywith CHOP alone: results of a prospective randomized study of theGerman Low-Grade Lymphoma Study Group. Blood.2005;106(12):3725–32.

6. Armitage JO, Bociek RG. Increasing complexity of high-grade B-cell lymphomas. Cancer. 2014;120(11):1611–3.

7. Armitage JO. How I, treat patients with diffuse large B-cell lym-phoma. Blood. 2007;110(1):29–36.

8. Lazarus HM, Zhang MJ, Carreras J, Hayes-Lattin BM, AtaerginAS, Bitran JD, et al. A comparison of HLA-identical sibling allo-geneic versus autologous transplantation for diffuse large B cell

Curr Hematol Malig Rep

lymphoma: a report from the CIBMTR. Biol Blood MarrowTransplant. 2010;16(1):35–45.

9. van Besien K, Loberiza Jr FR, Bajorunaite R, Armitage JO, BasheyA, Burns LJ, et al. Comparison of autologous and allogeneic hema-topoietic stem cell transplantation for follicular lymphoma. Blood.2003;102(10):3521–9.

10. Ganti AK, Bierman PJ, Lynch JC, Bociek RG, Vose JM, ArmitageJO. Hematopoietic stem cell transplantation in mantle cell lympho-ma. Ann Oncol. 2005;16(4):618–24.

11. Smith SM, Burns LJ, van Besien K, Lerademacher J, HeW, FenskeTS, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J Clin Oncol. 2013;31(25):3100–9.

12. Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA,Horowitz MM, et al. Autologous versus reduced-intensity alloge-neic hematopoietic cell transplantation for patients withchemosensitive follicular non-Hodgkin lymphoma beyond firstcomplete response or first partial response. Biol Blood MarrowTransplant. 2011;17(7):1051–7.

13.• Fenske TS, Zhang MJ, Carreras J, Ayala E, Burns LJ, Cashen A, etal. Autologous or reduced-intensity conditioning allogeneic hema-topoietic cell transplantation for chemotherapy-sensitivemantle-celllymphoma: analysis of transplantation timing and modality. J ClinOncol. 2014;32(4):273–81. This large retrospective study com-pares the results of autologous and reduced intensity condition-ing allogeneic transplantation for chemotherapy-sensitive man-tle cell lymphoma.

14. Ghobadi A, Nolley E, Liu J, McBride A, Stockerl-Goldstein K,Cashen A. Retrospective comparison of allogeneic vs autologoustransplantation for diffuse large B-cell lymphoma with early relapseor primary induction failure. Bone Marrow Transplant. 2015;50(1):134–6.

15. Bhatt VR, Loberiza Jr FR, Jing H, Bociek RG, Bierman PJ, ManessLJ, et al. Mortality patterns among recipients of autologous hema-topoietic stem cell transplantation for lymphoma and myeloma inthe past three decades. Clin Lymphoma Myeloma Leuk.2015;15(7):409–15.

16. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, MaloneyDG, et al. Hematopoietic cell transplantation (HCT)-specific co-morbidity index: a new tool for risk assessment before allogeneicHCT. Blood. 2005;106(8):2912–9.

17. Sorror M, Storer B, Gopal A, Holmberg L, Sandmaier BM,Bensinger WI, et al. Comorbidity, lactate dehydrogenase (LDH),and chemosensitivity are independent predictors of mortality afterautologous hematopoietic cell transplantation (HCT) for patients(pts) with lymphoma. ASH Annual Meeting Abstract.2007;110(11):616.

18. Hari P, Carreras J, Zhang MJ, Gale RP, Bolwell BJ, Bredeson CN,et al. Allogeneic transplants in follicular lymphoma: higher risk ofdisease progression after reduced-intensity compared tomyeloablative conditioning. Biol Blood Marrow Transplant.2008;14(2):236–45.

19. Muffly LS, Boulukos M, Swanson K, Kocherginsky M, Cerro PD,Schroeder L, et al. Pilot study of comprehensive geriatric assess-ment (CGA) in allogeneic transplant: CGA captures a high preva-lence of vulnerabilities in older transplant recipients. Biol BloodMarrow Transplant. 2013;19(3):429–34.

20. Holmes HM, Des Bordes JK, Kebriaei P, Yennu S, Champlin RE,Giralt S, et al. Optimal screening for geriatric assessment in olderallogeneic hematopoietic cell transplantation candidates. J GeriatrOncol. 2014;5(4):422–30.

21. Muffly LS, KocherginskyM, StockW, Chu Q, BishopMR,GodleyLA, et al. Geriatric assessment to predict survival in older alloge-neic hematopoietic cell transplantation recipients. Haematologica.2014;99(8):1373–9.

22. Bacher U, Klyuchnikov E, Le-Rademacher J, Carreras J, Armand P,Bishop MR, et al. Conditioning regimens for allotransplants for

diffuse large B-cell lymphoma: myeloablative or reduced intensity?Blood. 2012;120(20):4256–62.

23.• Hamadani M, Saber W, Ahn KW, Carreras J, CairoMS, Fenske TS,et al. Allogeneic hematopoietic cell transplantation forchemotherapy-unresponsive mantle cell lymphoma: a cohort anal-ysis from the center for international blood and marrow transplantresearch. Biol Blood Marrow Transplant. 2013;19(4):625–31. Thislarge retrospective study compares the results of myeloablativeversus non-myeloablative/reduced intensity conditioning allo-geneic transplantation for refractory mantle cell lymphoma.

24.• Hamadani M, Saber W, Ahn KW, Carreras J, CairoMS, Fenske TS,et al. Impact of pretransplantation conditioning regimens on out-comes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B cell lymphoma and grade III follicularlymphoma. Biol Blood Marrow Transplant. 2013;19(5):746–53.This large retrospective study compares the results ofmyeloablative versus non-myeloablative/reduced intensity con-ditioning allogeneic transplantation for refractory diffuse largeB cell lymphoma and grade III follicular lymphoma.

25. Rodriguez R, Nademanee A, Ruel N, Smith E, Krishnan A,Popplewell L, et al. Comparison of reduced-intensity and conven-tional myeloablative regimens for allogeneic transplantation innon-Hodgkin’s lymphoma. Biol Blood Marrow Transplant.2006;12(12):1326–34.

26. Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW,et al. Phase II study of allogeneic transplantation for older patientswith acute myeloid leukemia in first complete remission using areduced-intensity conditioning regimen: results from cancer andleukemia group B 100103 (alliance for clinical trials in oncology)/blood and marrow transplant clinical trial network 0502. J ClinOncol. 2015.

27. Kasamon YL, Bolanos-Meade J, Prince GT, Tsai HL, McCurdySR, Kanakry JA, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dosepost-transplantation cyclophosphamide in older adults. J ClinOncol. 2015;33(28):3152–61.

28. Gyurkocza B, Sandmaier BM. Conditioning regimens for hemato-poietic cell transplantation: one size does not fit all. Blood.2014;124(3):344–53.

29. Akhtari M, Bhatt VR, Tandra PK, Krishnamurthy J, Horstman H,Dreessen A, et al. Therapy-related myeloid neoplasms after autol-ogous hematopoietic stem cell transplantation in lymphoma pa-tients. Cancer Biol Ther. 2013;14(12):1077–88.

30. Armitage JO, Carbone PP, Connors JM, Levine A, Bennett JM,Kroll S. Treatment-related myelodysplasia and acute leukemia innon-Hodgkin’s lymphoma patients. J Clin Oncol. 2003;21(5):897–906.

31. Litzow MR, Perez WS, Klein JP, Bolwell BJ, Camitta B, CopelanEA, et al. Comparison of outcome following allogeneic bone mar-row transplantation with cyclophosphamide-total body irradiationversus busulphan-cyclophosphamide conditioning regimens foracute myelogenous leukaemia in first remission. Br J Haematol.2002;119(4):1115–24.

32. HartmanAR,Williams SF, Dillon JJ. Survival, disease-free survivaland adverse effects of conditioning for allogeneic bone marrowtransplantation with busulfan/cyclophosphamide vs total body irra-diation: a meta-analysis. Bone Marrow Transplant. 1998;22(5):439–43.

33. Nagler A, Rocha V, Labopin M, Unal A, Ben Othman T, CamposA, et al. Allogeneic hematopoietic stem-cell transplantation foracute myeloid leukemia in remission: comparison of intravenousbusulfan plus cyclophosphamide (Cy) versus total-body irradiationplus Cy as conditioning regimen—a report from the acute leukemiaworking party of the European group for blood and marrow trans-plantation. J Clin Oncol. 2013;31(28):3549–56.

Curr Hematol Malig Rep

34. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, ZhuX, et al. Better leukemia-free and overall survival in AML in firstremission following cyclophosphamide in combination with busul-fan compared with TBI. Blood. 2013;122(24):3863–70.

35. Bredeson C, LeRademacher J, Kato K, Dipersio JF, Agura E,Devine SM, et al. Prospective cohort study comparing intravenousbusulfan to total body irradiation in hematopoietic cell transplanta-tion. Blood. 2013;122(24):3871–8.

36. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, et al.Randomized trial of myeloablative conditioning regimens: busulfanplus cyclophosphamide versus busulfan plus fludarabine. J ClinOncol. 2013;31(6):701–9.

37. Liu H, Zhai X, Song Z, Sun J, Xiao Y, Nie D, et al. Busulfan plusfludarabine as a myeloablative conditioning regimen comparedwith busulfan plus cyclophosphamide for acute myeloid leukemiain first complete remission undergoing allogeneic hematopoieticstem cell transplantation: a prospective and multicenter study. JHematol Oncol. 2013;6:15.

38. Rambaldi A, Grassi A, Masciulli A, Boschini C, Mico MC, BuscaA, et al. Busulfan plus cyclophosphamide versus busulfan plusfludarabine as a preparative regimen for allogeneic haemopoieticstem-cell transplantation in patients with acute myeloid leukaemia:an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol.2015;16(15):1525–36.

39. Gopal AK, Gooley TA, Rajendran JG, Pagel JM, Fisher DR,Maloney DG, et al. Myeloablative I-131-tositumomab with esca-lating doses of fludarabine and autologous hematopoietic transplan-tation for adults age ≥ 60 years with B cell lymphoma. Biol BloodMarrow Transplant. 2014;20(6):770–5.

40. Press OW, Unger JM, Rimsza LM, Friedberg JW, LeBlanc M,Czuczman MS, et al. Phase III randomized intergroup trial ofCHOP Plus rituximab compared with CHOP chemotherapy plus131iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol. 2013;31(3):314–20.

41. Scholz CW, Pinto A, Linkesch W, Lindén O, Viardot A, Keller U,et al. 90Yttrium-ibritumomab-tiuxetan as first-line treatment for follic-ular lymphoma: 30 months of follow-up data from an internationalmulticenter phase II clinical trial. J Clin Oncol. 2013;31(3):308–13.

42. Decaudin D, Mounier N, Tilly H, Ribrag V, Ghesquieres H,Bouabdallah K, et al. (90)Y ibritumomab tiuxetan (Zevalin) com-bined with BEAM (Z-BEAM) conditioning regimen plus autolo-gous stem cell transplantation in relapsed or refractory low-gradeCD20-positive B-cell lymphoma. A GELA phase II prospectivestudy. Clin Lymphoma Myeloma Leuk. 2011;11(2):212–8.

43. Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Rand A,et al. Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation(SCT) in patients with chemorefractory non-Hodgkin’s lymphoma.Bone Marrow Transplant. 2008;41(4):355–61.

44. Bethge WA, Lange T, Meisner C, von Harsdorf S, Bornhaeuser M,Federmann B, et al. Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced- intensity conditioningregimen for allogeneic hematopoietic cell transplantation in patientswith advanced non-Hodgkin lymphoma: results of a phase 2 study.Blood. 2010;116(10):1795–802.

45. Abou-Nassar KE, Stevenson KE, Antin JH, McDermott K, Ho VT,Cutler CS, et al. (90)Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo-SCT in patients with advanced fol-licular lymphoma. Bone Marrow Transplant. 2011;46(12):1503–9.

46. Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M,Medeiros LJ, et al. Nonmyeloablative allogeneic transplantationwith or without 90yttrium ibritumomab tiuxetan is potentially cu-rative for relapsed follicular lymphoma: 12-year results. Blood.2012;119(26):6373–8.

47. Vose JM, Bierman PJ, Loberiza FR, Enke C,Hankins J, Bociek RG,et al. Phase II trial of 131-Iodine tositumomab with high-dose che-motherapy and autologous stem cell transplantation for relapseddiffuse large B cell lymphoma. Biol Blood Marrow Transplant.2013;19(1):123–8.

48. Vose JM, Bierman PJ, Enke C, Hankins J, Bociek G, Lynch JC,et al. Phase I trial of iodine-131 tositumomab with high-dose che-motherapy and autologous stem-cell transplantation for relapsednon-Hodgkin’s lymphoma. J Clin Oncol. 2005;23(3):461–7.

49. Press OW, Eary JF, Gooley T, Gopal AK, Liu S, Rajendran JG, et al.A phase I/II trial of iodine-131-tositumomab (anti-CD20),etoposide, cyclophosphamide, and autologous stem cell transplan-tation for relapsed B-cell lymphomas. Blood. 2000;96(9):2934–42.

50. Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH,et al. Phase III randomized study of rituximab/carmustine,etoposide, cytarabine, and melphalan (BEAM) compared withiodine-131 tositumomab/BEAM with autologous hematopoieticcell transplantation for relapsed diffuse large B-cell lymphoma:results from the BMT CTN 0401 trial. J Clin Oncol. 2013;31(13):1662–8.

51. Ho VT, Soiffer RJ. The history and future of T-cell depletion asgraft-versus-host disease prophylaxis for allogeneic hematopoieticstem cell transplantation. Blood. 2001;98(12):3192–204.

52. Delgado J, Canals C, Attal M, Thomson K, Campos A, Martino R,et al. The role of in vivo T-cell depletion on reduced-intensity con-ditioning allogeneic stem cell transplantation from HLA-identicalsiblings in patients with follicular lymphoma. Leukemia.2011;25(3):551–5.

53. Thomson KJ,Morris EC,Milligan D, Parker AN, Hunter AE, CookG, et al. T-cell-depleted reduced-intensity transplantation followedby donor leukocyte infusions to promote graft-versus-lymphomaactivity results in excellent long-term survival in patients with mul-tiply relapsed follicular lymphoma. J Clin Oncol. 2010;28(23):3695–700.

54. Ingram W, Devereux S, Das-Gupta EP, Russell NH, Haynes AP,Byrne JL, et al. Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stagefollicular lymphoma. Br J Haematol. 2008;141(2):235–43.

55. Freytes CO, Loberiza FR, Rizzo JD, Bashey A, Bredeson CN, CairoMS, et al.Myeloablative allogeneic hematopoietic stem cell transplan-tation in patients who experience relapse after autologous stem celltransplantation for lymphoma: a report of the International BoneMarrowTransplant Registry. Blood. 2004;104(12):3797–803.

56. van Kampen RJ, Canals C, Schouten HC, Nagler A, Thomson KJ,Vernant JP, et al. Allogeneic stem-cell transplantation as salvagetherapy for patients with diffuse large B-cell non-Hodgkin’s lym-phoma relapsing after an autologous stem-cell transplantation: ananalysis of the European Group for Blood and MarrowTransplantation Registry. J Clin Oncol. 2011;29(10):1342–8.

57. Rezvani AR, Kanate AS, Efron B, Chhabra S, Kohrt HE, ShizuruJA, et al. Allogeneic hematopoietic cell transplantation after failedautologous transplant for lymphoma using TLI and anti-thymocyteglobulin conditioning. Bone Marrow Transplant. 2015;50(10):1286–92.

58. Cohen S, Kiss T, Lachance S, Roy DC, Sauvageau G, Busque L,et al. Tandem autologous-allogeneic nonmyeloablative siblingtransplantation in relapsed follicular lymphoma leads to impressiveprogression-free survival with minimal toxicity. Biol BloodMarrow Transplant. 2012;18(6):951–7.

59.• Chen YB, Li S, Fisher DC, Driscoll J, Del Rio C, Abramson J, et al.Phase II trial of tandem high-dose chemotherapy with autologousstem cell transplantation followed by reduced-intensity allogeneicstem cell transplantation for patients with high-risk lymphoma. BiolBlood Marrow Transplant. 2015;21(9):1583–8. This phase II trialdemonstrates promising results with tandem transplant strate-gy in high-risk lymphoma.

Curr Hematol Malig Rep

60. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR,Aljitawi OS, et al. Haploidentical transplant with posttransplantcyclophosphamide vs matched unrelated donor transplant for acutemyeloid leukemia. Blood. 2015;126(8):1033–40.

61. Gaballa S, Palmisiano N, Alpdogan O, Carabasi M, Filicko-O’Hara J,Kasner M, et al. A two-step haploidentical versus a two-step matchedrelatedallogeneicmyeloablativeperipheral blood stemcell transplanta-tion. Biol BloodMarrowTransplant. 2016;22(1):141–8.

62. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S,Holland HK, et al. Total body irradiation-based myeloablativehaploidentical stem cell transplantation is a safe and effective alter-native to unrelated donor transplantation in patients withoutmatched sibling donors. Biol Blood Marrow Transplant.2015;21(7):1299–307.

63. Rodrigues CA, Sanz G, Brunstein CG, Sanz J, Wagner JE, RenaudM, et al. Analysis of risk factors for outcomes after unrelated cordblood transplantation in adults with lymphoid malignancies: a studyby the Eurocord-Netcord and lymphoma working party of theEuropean group for blood and marrow transplantation. J ClinOncol. 2009;27(2):256–63.

64. Roberto C, Sabine F, Stefania B, Barbara S, Angela G, Catherine F,et al. Comparison of umbilical cord blood and haploidentical donorgrafts in adults with high risk hematologic diseases after fludarabinecyclophosphamide and TBI 2 Gy based reduced-intensity condition-ing regimen stem cell transplantation. Blood. 2013;122(21):3288.

65. Horan JT, Logan BR, Agovi-Johnson MA, Lazarus HM,Bacigalupo AA, Ballen KK, et al. Reducing the risk fortransplantation-related mortality after allogeneic hematopoietic celltransplantation: how much progress has been made? J Clin Oncol.2011;29(7):805–13.

66. Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, WingardJR, et al. Peripheral-blood stem cells versus bone marrow fromunrelated donors. N Engl J Med. 2012;367(16):1487–96.

67. McCurdy SR, Kanakry JA, ShowelMM, Tsai H-L, Bolaños-MeadeJ, Rosner GL, et al. Risk-stratified outcomes of nonmyeloablativeHLA-haploidentical BMT with high-dose posttransplantation cy-clophosphamide. Blood. 2015;125(19):3024–31.

68. Al-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U. Post-transplanthigh-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(4):604–11.

69. Reshef R, Huffman AP, Gao A, Luskin MR, Frey NV, Gill SI, et al.High graft CD8 cell dose predicts improved survival and enablesbetter donor selection in allogeneic stem-cell transplantation withreduced-intensity conditioning. J Clin Oncol. 2015;33(21):2392–8.

70. Ferro RA, Bhatt VR, Smith L, LunningMA, Bierman PJ, ArmitageJO, Bociek G, Vose J Long-term outcomes of rituximab use prior toautologous stem cell transplant (ASCT) in low-grade follicular lym-phoma (FL) at the time of first progression ASCO 2015 AnnualMeeting May 29-June 2, 2015 Chicago

71. Vose JM, Bierman PJ, Loberiza FR, Lynch JC, Bociek GR,Weisenburger DD, et al. Long-term outcomes of autologous stemcell transplantation for follicular non-Hodgkin lymphoma: effect ofhistological grade and follicular international prognostic index.Biol Blood Marrow Transplant. 2008;14(1):36–42.

72. NademaneeA,PalmerJM,PopplewellL,TsaiNC,DelioukinaM,GaalK,etal.High-dosetherapyandautologoushematopoieticcell transplan-tation in peripheral T cell lymphoma (PTCL): analysis of prognosticfactors. Biol BloodMarrowTransplant. 2011;17(10):1481–9.

73. Cook G, Smith GM, Kirkland K, Lee J, Pearce R, Thomson K, et al.Outcome following reduced-intensity allogeneic stem cell transplanta-tion (RIC AlloSCT) for relapsed and refractory mantle cell lymphoma(MCL): a study of the British Society for Blood and MarrowTransplantation.BiolBloodMarrowTransplant. 2010;16(10):1419–27.

74. Reimer P, Rudiger T, Geissinger E, Weissinger F, Nerl C, SchmitzN, et al. Autologous stem-cell transplantation as first-line therapy in

peripheral T-cell lymphomas: results of a prospective multicenterstudy. J Clin Oncol. 2009;27(1):106–13.

75. Arcaini L, Montanari F, Alessandrino EP, Tucci A, Brusamolino E,Gargantini L, et al. Immunochemotherapy with in vivo purging andautotransplant induces long clinical and molecular remission in ad-vanced relapsed and refractory follicular lymphoma. Ann Oncol.2008;19(7):1331–5.

76. Morschhauser F, Recher C, Milpied N, Gressin R, Salles G, Brice P,et al. A 4-weekly course of rituximab is safe and improves tumorcontrol for patients with minimal residual disease persisting 3months after autologous hematopoietic stem-cell transplantation:results of a prospective multicenter phase II study in patients withfollicular lymphoma. Ann Oncol. 2012;23(10):2687–95.

77. Hicks LK, Woods A, Buckstein R, Mangel J, Pennell N, Zhang L,et al. Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolongedhypogammaglobulinemia in relapsed follicular lymphoma. BoneMarrow Transplant. 2009;43(9):701–8.

78. Brugger W, Hirsch J, Grunebach F, Repp R, Brossart P, Vogel W, etal. Rituximab consolidation after high-dose chemotherapy and au-tologous blood stem cell transplantation in follicular and mantle celllymphoma: a prospective, multicenter phase II study. Ann Oncol.2004;15(11):1691–8.

79. Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B, et al.Phase I trial of maintenance sorafenib after allogeneic hematopoi-etic stem cell transplantation for fms-like tyrosine kinase 3 internaltandem duplication acute myeloid leukemia. Biol Blood MarrowTransplant. 2014;20(12):2042–8.

80. Antar A, Kharfan-Dabaja MA, Mahfouz R, Bazarbachi A.Sorafenib maintenance appears safe and improves clinical out-comes in FLT3-ITD acute myeloid leukemia after allogeneic he-matopoietic cell transplantation. Clin Lymphoma Myeloma Leuk.2015;15(5):298–302.

81.• Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M,Gramatzki M, et al. Rituximab after lymphoma-directed condition-ing and allogeneic stem-cell transplantation for relapsed and refrac-tory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014;15(7):757–66.This phase II trial demonstrates a lack of survival benefit withrituximab maintenance after allogeneic transplantation inNHL; many patients were previously exposed to rituximab.

82. Chen R, Palmer JM, Tsai NC, Thomas SH, Siddiqi T, Popplewell L,et al. Brentuximab vedotin is associated with improvedprogression-free survival after allogeneic transplantation forHodgkin lymphoma. Biol Blood Marrow Transplant.2014;20(11):1864–8.

83. WilsonWH, YoungRM, Schmitz R, Yang Y, Pittaluga S,Wright G,et al. Targeting B cell receptor signaling with ibrutinib in diffuselarge B cell lymphoma. Nat Med. 2015;21:922–6.

84. Sehn LH, Chua NS, Mayer J, Dueck GS, et al. GADOLIN: primaryresults from a phase III study of obinutuzumab plus bendamustinecompared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. ASCO Meet Abstr.2015;33(15_suppl):LBA8502. Trn, #x011B.

85. Salles GA, Schuster SJ, De Vos S, Wagner-Johnston ND, ViardotA, Flowers C, et al. Idelalisib efficacy and safety in follicular lym-phoma patients from a phase 2 study. ASCO Meet Abstr.2015;33(15_suppl):8529.

86. Davids MS, Seymour JF, Gerecitano JF, Kahl BS, Pagel JM,Wierda WG, et al. Phase I study of ABT-199 (GDC-0199) in pa-tients with relapsed/refractory (R/R) non-Hodgkin lymphoma(NHL): responses observed in diffuse large B-cell (DLBCL) andfollicular lymphoma (FL) at higher cohort doses. ASCO MeetAbstr. 2014;32(15_suppl):8522.

87. Advani RH, Flinn I, Sharman JP, Magid Diefenbach CS, KolibabaKS, Press OW, et al. Two doses of polatuzumab vedotin (PoV, anti-

Curr Hematol Malig Rep

CD79b antibody-drug conjugate) in patients (pts) with relapsed/refractory (RR) follicular lymphoma (FL): durable responses atlower dose level. ASCO Meet Abstr. 2015;33(15_suppl):8503.

88. Kimby E, Martinelli G, Ostenstad B, Mey UJ, Rauch D, WahlinBE, et al. Rituximab plus lenalidomide improves the complete re-mission rate in comparison with rituximab monotherapy in untreat-ed follicular lymphoma patients in need of therapy. Primary end-point analysis of the randomized phase-2 trial SAKK 35/10. Blood.2014;124(21):799.

89. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A,Gutierrez M, et al. Preliminary results of a phase I study ofnivolumab (BMS-936558) in patients with relapsed or refractorylymphoid malignancies. Blood. 2014;124(21):291.

90. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RPT,Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell ma-lignancies can be effectively treated with autologous T cells

expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol.2015;33(6):540–9.

91. Savani BN, Griffith ML, Jagasia S, Lee SJ. How I treat late effectsin adults after allogeneic stem cell transplantation. Blood.2011;117(11):3002–9.

92. Burns LJ. Late effects after autologous hematopoietic cell trans-plantation. Biol BloodMarrow Transplant. 2009;15(1 Suppl):21–4.

93. Hill BT, Rybicki L, Bolwell BJ, Smith S, Dean R, KalaycioM, et al.The non-relapse mortality rate for patients with diffuse large B-celllymphoma is greater than relapse mortality 8 years after autologousstem cell transplantation and is significantly higher than mortalityrates of population controls. Br J Haematol. 2011;152(5):561–9.

94. Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, et al.Recommended screening and preventive practices for long-termsurvivors after hematopoietic cell transplantation. Biol BloodMarrow Transplant. 2012;18(3):348–71.

Curr Hematol Malig Rep