L

J

LNiAetFfs(hdcpayIfB

©3

T

ow-Grade Lymphoma: The Optimal Timing

. Gibson, P.J. Ho, and D. Joshua

ABSTRACT

The median survival of patients with follicular lymphoma (FL), the most frequentlow-grade non-Hodgkin’s lymphoma, is 7 to 10 years with most patients exhibiting apattern of relapsing disease and increasing drug resistance. The subset with poorestprognostic features, however, has a median survival of less than 2 years. The failure ofconventional chemotherapy to cure such patients has led to the evaluation of high-dosetherapy (HDT) and hemopoietic stem cell transplantation. Although no large randomizedtrials have been performed, historical comparisons within individual centers as well asregistry analysis appear to support HDT with autologous stem cell support in patients withrelapsed and refractory FL. Appropriate patient selection on the basis of prognosticmarkers as well as transplantation earlier in the course of the disease have been identifiedas key issues that predict the success of transplantation in these patients. HDT withautologous support as part of planned initial therapy or in first remission has also been thesubject of a number of studies including at least two large randomized trials. Althoughpreliminary analyses suggest an advantage in the HDT approach, longer follow-up will berequired before definitive conclusions can be drawn. A variety of purging strategies havebeen evaluated for autologous transplants but results are still inconclusive. Allogeneictransplantation is an option for selected patients, although its wider application isrestricted by transplant-related complications. Experience with nonmyeloablative condi-tioning strategies is limited, and as yet the expectation of a reduction of transplant-related

morbidity and mortality remains to be demonstrated.

gamyIsbmatpoac

p

t

OW-GRADE NON-HODGKIN’S LYMPHOMAS(NHL), which account for approximately one-third of

HL, are a heterogeneous group of disorders with an oftenndolent but potentially highly variable clinical course.lthough frequently responsive to therapy, there is a gen-

ral pattern of relapsing disease and increasing resistance toreatment. Most patients eventually die of their disease.urthermore, patients with advanced or aggressive disease

requently progress after initial treatment and have limitedurvival.1,2 The assessment of the role of high-dose therapyHDT) and transplantation in low-grade NHL (LGL) isampered by the heterogeneous nature of this group ofiseases, and this review will primarily focus on the mostommon form (�70%), follicular lymphoma (FL), a neo-lasm of follicle center B lymphocytes. FL principallyffects adults (median age 59) and is rare in individuals �20ears of age. Two-thirds to three-quarters of cases are stageII to IV at diagnosis and the clinical features vary widelyrom asymptomatic to the presence of marked systemic (ie,

) symptoms.2,3 Histological transformation to a higher- A

2004 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 36, 1995–1998 (2004)

rade NHL occurs in a significant proportion of patientsnd is associated with a very poor outlook. Although theedian survival of FL in general is in the range of 7 to 10

ears, the subset with the poorest prognostic features (highnternational Prognostic Index, IPI, etc) has a medianurvival of �2 years. Although truly localized disease maye cured by initial radiotherapy and/or chemotherapy, theajority of cases have traditionally been considered incur-

ble. Hence the increasing interest in HDT and transplan-ation options, which may offer selected individuals theossibility of long disease-free survival (DFS).4 An impactn overall survival (OS), however, is yet to be convincinglynd repeatedly demonstrated. A variety of factors compli-ate the demonstration of an impact of HDT and transplan-

From the Institute of Haematology, Royal Prince Alfred Hos-ital; Camperdown, Australia.Address reprint requests to John Gibson, Institute of Haema-

ology, Royal Prince Alfred Hospital, Camperdown, NSW 2050,

ustralia.E-mail: jgibson@haem.rpa.cs.nsw.gov.au

0041-1345/04/$–see front matterdoi:10.1016/j.transproceed.2004.06.034

1995

taosttlaaogto

wrEoilriprcgrrp(FbBcytncfefir

ltTpp5tcafftIw

3tsgr(p(cwt

ppecrtcsrydTlcfwwcIpsppya

btO.rl(2rhi(m(5ttf

1996 GIBSON, HO AND JOSHUA

ation on OS in FL. Such variables include the high mediange, an indolent clinical course, the potential for high ratesf transplant-related and other long-term complications,uch as secondary myelodysplasia and acute leukaemia (upo 20% at 10 years),5 and the emergence of newer poten-ially highly effective therapies such as nucleoside ana-ogues, monoclonal antibodies, antisense oligonucleotides,nd vaccination strategies. The variety of HDT options suchs the type of transplant, source of stem cells (SC), timingf transplant, preparative regimen, purging of autologousrafts, as well as full dose versus reduced intensity condi-ioning allogeneic protocols similarly confound assessmentf transplant studies.The first groups of FL patients in whom the role of HDT

as addressed were those who had undergone multipleelapses, often with highly drug-resistant residual disease.xperience from single centers demonstrated the feasibilityf HDT and autologous stem cell rescue and evaluated the

mpact of purging strategies. Apostolidis et al6 reportedong-term follow-up of 99 patients in second or subsequentemission who received cyclophosphamide and total bodyrradiation (TBI) (cyclo/TBI) conditioning followed by aurged (mostly anti-CD20 antibody) autologous bone mar-ow transplant (BMT). Comparison with matched historicalontrols demonstrated an advantage in favor of the HDTroup (P � .001). Absence of detectable Bc12-IgH rear-angement during follow-up was associated with a lowerisk of recurrence (P � .001) and death (P � .02). Theolymerase chain reaction (PCR) status of the infusedpurged) bone marrow did not affect outcome. The Danaaber group reported 153 heavily pretreated patients who,etween 1985 and 1995, underwent a purged autologousMT using a cocktail of monoclonal antibodies followingyclo/TBI.7 Estimated DFS and OS of 42% and 66% at 8ears were reported. Bone marrow negativity by PCR forhe Bcl2-IgH fusion gene after purging and continuedegativity post-HDT was associated with longer DFS andontinued complete remission (CR). The median survivalrom diagnosis in all patients was 12 years, which wasstimated to be superior to the median survivals followingrst recurrence (5 years) and diagnosis (8 years) of compa-able patients with advanced FL.

A somewhat similar OS has been reported from thearge registry study recently published by the Interna-ional Bone Marrow and Autologous Blood and Marrowransplant Registries (IBMTR and ABMTR).8 Five-yearrobabilities of OS (95% confidence intervals), forurged (n � 131) and unpurged autotransplants (n �97) were 62% (53 to 75) and 55% (50 to 60), respec-ively. Multivariate analysis identified advanced stage,hemoresistance, lactic acid dehydrogenase (LDH), age,nd a prolonged delay before transplantation as adverseactors. The GELF group has also reported an advantageor HDT in a subset of relapsing/progressing LGL pa-ients enrolled in their GELF86 trial of primary therapy.n a retrospective analysis they compared those patients

ho underwent HDT for management of relapse (22% of v

72) with those who received “standard” therapy. Al-hough the assignment to HDT was not randomized, aignificant advantage in OS was reported for the HDTroup (P � .002).9 Finally, preliminary results from theandomized, but poorly accruing, European CUP trialChemotherapy vs Unpurged vs Purged HDT) in 140atients with relapsed FL have suggested that HDTunpurged or purged) improves progression-free survivalompared to the C arm (P � .01). No survival advantageas seen (P � .31), nor was there a difference between

he purged and unpurged arms.10

HDT and autologous stem cell transplant (SCT), asart of planned initial therapy or in first CR or very goodartial remission (PR), is a natural extension of thefficacy of this approach in relapsed patients. Clearly it isrucial to be able to identify those patients in whom aeduced OS would warrant the use of such aggressiveherapy early in the course of their disease. Such patientsan be identified using a variety of prognostic factorsuch as the FL-modified IPI.11 The Stanford group12

eported a phase II trial in which 37 patients (age �60ears and at least one IPI risk factor) with minimalisease after initial chemotherapy received fractionatedBI, high-dose cyclophosphamide, and etoposide fol-

owed by a purged autologous BMT. These patients wereompared to a reference group of 188 matched patientsrom the same institution. A trend for a longer survivalas reported in the transplant group, particularly thoseith a high tumor burden, although this was not statisti-ally significant (10-years OS 59% vs 86%, P � .74). Thetalian GITMO group has reported the results of arospective single-arm multicenter study of high-doseequential therapy and postulated in vivo purging sup-orted by peripheral blood SC rescue at diagnosis inatients with high-risk FL. Projected OS and DFS at 4ears were 84% and 67%.13 The DFS for those whochieved molecular remission was 85%.At least two large multicenter randomized studies have

een completed in this group.14 Seven-year follow-up ofhe GELF94 randomized trial reports an advantage forS (P � .05) but not event-free survival (EFS) (P �

28)14 in HDT patients (n � 192) compared to those whoeceived maintenance interferon-alpha (n � 207). Pre-iminary results of the German low-grade lymphomaLGL) study have been presented (Hiddermann, Sydney003). Of 571 patients achieving complete or partialemission following initial CHOP chemotherapy, threeundred thirty-five were randomized to maintenance

nterferon-alpha or HDT. Median event-free survivalEFS) of the interferon-alpha group is less than 25onths although it exceeds 60 months for the HDT arm

P � .0005). In contrast, another German group reported5 advanced-stage FL patients who underwent HDTherapy with peripheral blood SC rescue as upfrontherapy (n � 33) or salvage (n � 22). When calculatedrom diagnosis the EFS and OS of the two groups were

irtually identical.15

atnBsraidtiRrwitcvtviptat

ugttoIHpacro

TolAwcmtsATcFs(

o

opilnpprthsc

R

pHP

n

ss

tO

pmc

trf

fw

ot

wgc

iHt

p

apt

ahAM

im

LOW-GRADE LYMPHOMA 1997

A variety of purging techniques including anti-B-cellntibodies (naked and conjugated), drug purging, posi-ive CD34� selection as well as combined positive andegative selection, have been reported.4 The series fromoston,7 Standford,12 and the IBMTR/ABMTR analysis8

uggest support for purging although the London expe-ience6 and the small CUP trial10 do not suggest andvantage. Of note the recently completed large random-zed trials did not evaluate the utility of purging. Oneisadvantage of purging is that much of the requiredechnology is expensive and often of restricted availabil-ty outside the developing center or other large centers.ecent interest therefore has focused on the use of the

eadily available anti-CD20 monoclonal (Rituximab),hich is currently being evaluated in a variety of in vivo,

n vitro, and ex vivo strategies such as the current EBMTrial.16 Alternative novel approaches include the GITMOoncept of high-dose sequential chemotherapy with inivo purging as well as a recent report of radioimmuno-herapy from Seattle. In the latter study, a multipleariable comparison of 125 consecutive but not random-zed FL patients, they reported superior 5-year OS androgression-free survivals for high-dose radioimmuno-herapy (131I-anti-CD20) over conventional HDT andutologous SCT (67% and 48% vs 53% and 29%, respec-ively).17

The potential advantages of allogeneic SCT include anndamaged tumor-free source of SC and the potential for araft-versus-lymphoma effect. Transplant-related complica-ions (graft-versus-host-disease [GVHD] and mortality) inhis “older” group of patients have limited the applicationf conventional (full-dose, myeloablative) approaches. TheBMTR reported a large but heterogeneous series ofLA-identical sibling transplants with EFS of 49%, trans-

lant-related mortality (TRM) 40%, acute GVHD 27%,nd chronic GVHD 66%.18 Although plateaus on survivalurves have been suggested, no OS advantage has beeneported due to the high TRM. In their most recent analysisf FL the 5-year survival was 51% (43 to 69).8

Efforts to reduce toxicity of allogeneic transplants include-cell depletion and reduced intensity (nonmyeloablativer mini) conditioning.19 There is as yet only limited pub-

ished experience of reduced intensity conditioning in FL.n English collaborative group reported seven patientsho received Fludarabine, Melphalan, and Campathonditioning.20 With follow-up ranging from 3 to 27onths, four patients achieved CR, one PR, and there were

wo transplant-related deaths (28%). Nine reduced-inten-ity allogeneic transplants for FL have been reported to theustralasian Bone Marrow Transplant Recipient Registry.wo-year DFS is 65% and TRM at 1 year is 22%. Byomparison DFS was 65% and TRM 21% for a group of 20L patients with a similar median age who underwenttandard myeloablative transplants during the same periodGibson and Nivison-Smith, unpublished).

In summary, HDT with stem cell support is an attractive

ption for the subset of patients with FL (and potentially

t4

ther LGL) in whom a short median survival would beredicted. There is considerable support for this approach

n patients with relapsed/refractory disease as well as pre-iminary data from randomized studies in patients withewly diagnosed FL. The high TRM of allogeneic trans-lants has limited this approach to a small subset ofatients. As yet there is no convincing evidence for aeduced TRM, improved efficacy, and thus wider applica-ion for nonmyeloablative allogeneic transplants. Given theeterogeneous nature of survival in FL, appropriate patientelection for the various transplant options remains arucial issue.

EFERENCES

1. Nathwani B, Piris MA, Harris NL, et al: Follicular lym-homa. In Jaffe ES, Harris NL, Stein H, et al (eds): Tumours ofaematopoietic and Lymphoid Tissues. Lyon, France: IRACress; 20012. Horning SJ: Natural history and therapy for the indolent

on-Hodgkin’s lymphoma. Semin Oncol 20:75, 19933. Johnson PW, Rohatiner AZ, Whelan JS, et al: Patterns of

urvival in patients with recurrent follicular lymphoma: a 20-yeartudy from a single centre. J Clin Oncol 13:140, 1995

4. Berdeja JG, Flinn IW: New approaches to blood and marrowransplantation for patients with low-grade lymphomas. Currentpinion Oncol 13:335, 20015. Friedberg JW, Neuberg D, Stone RW, et al: Outcome in

atients with myelodysplastic syndrome after autologous bonearrow transplantation for non-Hodgkin’s lymphoma. J Clin On-

ol 17:3128, 19996. Apostolidis J, Gupta K, Grenzelias D, et al: High-dose

herapy with autologous bone marrow support as consolidation ofemission in follicular lymphoma: long-term clinical and molecularollow-up. J Clin Oncol 18:527, 2000

7. Freedman AS, Neuberg D, Mauch P, et al: Long-termollow-up of autologous bone marrow transplantation in patientsith relapsed follicular lymphoma. Blood 94:3325, 19998. van Besien K, Loberiza FR, Bajorunaite R, et al: Comparison

f autologous and allogeneic hematopoietic stem cell transplanta-ion for follicular lymphoma. Blood 102:3521, 2003

9. Brice P, Simon D, Bouabdallah R, et al: High-dose therapyith autologous stem-cell transplantation (ASCT) after first pro-ression. Prolonged survival of follicular lymphoma patients in-luded in the GELF96 protocol. Ann Oncol 11:1585, 2000

10. Schouten HC, Qian W, Sydes MR, et al: High dose therapymproves progression free survival in relapsed follicular non-

odgkin’s lymphoma (NHL): results from the randomised CUPrial. Ann Oncol 13:26, 2002 (abstract)

11. Solal Celigny P, Roy P: Follicular lymphoma internationalrognostic index (FLIPI). Ann Oncol 13:18, 2002 (abstract)12. Horning S, Negrin RS, Hoppe RT, et al: High-dose therapy

nd autologous bone marrow transplantation of follicular lym-homa in first complete or partial remission; results of a phase IIrial. Blood 97:404, 2001

13. Ladetto M, Corradini P, Vallet S, et al: High rate of clinicalnd molecular remissions in follicular lymphoma patients receivingigh-dose sequential chemotherapy and autografting at diagnosis.multicentre, prospective study by the Gruppo Italiano Trapiantoiddollo Osseo (GITMO). Blood 100:1559, 200214. Sebban C, Coiffier C, Belanger C, et al: A randomised trial

n follicular lymphoma comparing a standard chemotherapy regi-en with 4 courses of CHOP followed by an autologous stem cell

ransplant with TBI: the GELG94 trial from GELA. Hematol J:150, 2003

tp

A

ign2

b9

bm

pt

1998 GIBSON, HO AND JOSHUA

15. Seyfarth B, Kause R, Sonnen R, et al: Autologous stem cellransplantation for follicular lymphoma: no benefit for early trans-lant? Ann Hematol 80:398, 200116. European Group for Blood and Marrow Transplantation.ccessed August 24, 2004. Available from URL: www.ebmt.org17. Gopal AK, Gooley TA, Maloney DG, et al: High-dose radio-

mmunotherapy versus conventional high-dose therapy and autolo-ous hemopoietic stem cell transplantation for relapsed follicularon-Hodgkin’s lymphoma: a multivariable analysis. Blood 102:2351,

003 B

18. van Biesen K, Sobocinski K, Rowlings P, et al: Allogeneicone marrow transplantation for low grade lymphoma. Blood2:1832, 199819. Djulbegovic B, Seidenfeld J, Bonnell C, et al: Nonmyeloa-

lative allogeneic stem-cell transplantation for hematologicalignancies: a systematic review. Cancer Control 10:17, 200320. Chakraverty R, Peggs K, Chopra R, et al: Limiting trans-

lantation-related mortality following unrelated donor stem cellransplantation by using a nonmyeloablative conditioning regimen.

lood 99:1071, 2002