Terapia de alta dose e transplante autólogo de células-tronco na Macroglobulinemia de Waldenström

8/2/2019 Terapia de alta dose e transplante autlogo de clulas-tronco na Macroglobulinemia de Waldenstrm

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High-Dose Therapy and Autologous Stem-CellTransplantation in Waldenstrom Macroglobulinemia: TheLymphoma Working Party of the European Group forBlood and Marrow TransplantationCharalampia Kyriakou, Carmen Canals, David Sibon, Jean Yves Cahn, Majid Kazmi, William Arcese,Karin Kolbe, Norbert Claude Gorin, Kristy Thomson, Noel Milpied, Dietger Niederwieser, Karel Indrak,Paolo Corradini, Anna Sureda, and Norbert Schmitz

See accompanying article on page 2233

From the North West London National

Health Service Trust; Guys Hospital;

University College London Hospital,

London, United Kingdom; Lymphoma

Working Party; Hospital de la SantaCreu i Sant Pau, Barcelona, Spain;

Hopital St Louis; Ho pital Saint Antoine,

Paris; Ho pital Albert Michallon,

Grenoble; Centre Hospitalier Universi-

taire de Bordeaux, Pessac, France;

Rome Transplant Network, Rome;

University of Milano, Milano, Italy;

Johannes Gutenberg University, Mainz;

University Hospital Leipzig, Leipzig;

Asklepios Klinik St George, Hamburg,

Germany; and University Hospital,

Olomouc, Czech Republic.

Submitted June 10, 2009; accepted

December 11, 2009; published online

ahead of print at www.jco.org on April

5, 2010.

Written on behalf of the Lymphoma

Working Party of the European Group

for Blood and Marrow Transplantation.

Authors disclosures of potential con-

flicts of interest and author contribu-

tions are found at the end of this

article.

Corresponding author: Charalampia

Kyriakou, MD, PhD, North West

London, NHS Trust, Watford Rd,

Harrow, Middlessex, HA1 3UJ, United

Kingdom; e-mail: c.kyriakou@

btinternet.com.

2010 by American Society of ClinicalOncology

0732-183X/10/2813-2227/$20.00

DOI: 10.1200/JCO.2009.24.4905

A B S T R A C T

Purpose

The role of autologous stem-cell transplantation (ASCT) in Waldenstrom macroglobulinemia (WM)is not defined. The aim of this study was to analyze the results of ASCT in patients with WM andto determine the prognostic factors that have a significant impact on outcome.

Patients and MethodsWe analyzed 158 adult patients with WM reported to the European Group for Blood and MarrowTransplantation (EBMT) between January 1991 and December 2005. Median time from diagnosisto ASCT was 1.7 years (range, 0.3 to 20.3 years), 32% of the patients experienced treatmentfailure with at least three lines of therapy, and 93% had sensitive disease at the time of ASCT.Conditioning regimen was total-body irradiationbased in 45 patients. Median follow-up forsurviving patients was 4.2 years (range, 0.5 to 14.8 years).

ResultsNonrelapse mortality was 3.8% at 1 year. Ten patients developed a secondary malignancy, witha cumulative incidence of 8.4% at 5 years. Relapse rate was 52.1% at 5 years. Progression-freesurvival (PFS) and overall survival were 39.7% and 68.5%, respectively, at 5 years and were

significantly influenced by number of lines of therapy and chemorefractoriness at ASCT. Theachievement of a negative immunofixation after ASCT had a positive impact on PFS after ASCT.When used as consolidation at first response, ASCT provided a PFS of 44% at 5 years.

ConclusionASCT is a feasible procedure in young patients with advanced WM. ASCT should not be offered topatients with chemoresistant disease and to those who received more than three lines of therapy.

J Clin Oncol 28:2227-2232. 2010 by American Society of Clinical Oncology

INTRODUCTION

Waldenstrom macroglobulinemia (WM) is a lym-

phoproliferative disorder characterized by bonemarrow infiltration with lymphoplasmacytoid cells

and the presence of an immunoglobulin M (IgM)

monoclonal gammopathy.1 It is a rare disease with

reported median age at presentation ranging from

59 to 63 years. Median survival ranges between 60

and120months.2,3While approximately one fourth

of patients are asymptomatic and diagnosed by

chance,3,4 most are symptomatic and therefore re-

quire treatment.5,6 Until recently, first-line therapy

of WMwasbased on single-agent therapy with alky-

lating agents and nucleoside analogs. The overall

response rate for chlorambucil is approximately50%.7 The nucleoside analogs fludarabine and

cladribine areassociated withresponse rates ranging

from 40% to 90%, whereas rituximab induces re-

mission in about one third of the patients.8 Duringthe last 5 years, improved response rates have been

reported with the combination of two or three ofthese drugs or R-CHOP (rituximab plus cyclo-

phosphamide, doxorubicin, vincristine, and pred-

nisone).9,10 Nevertheless, in most studies thefollow-up is limited and, despite high initial re-

sponse rates, all patients eventually relapse. Clinical

results have been reported on the use of bort-ezomib,11 thalidomide,9and lenalidomide,12butthe

use of these and other new drugs is experimental at

this time.

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V OL UM E 2 8 N UM BE R 1 3 M A Y 1 2 0 1 0

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The roleof autologous stem-cell transplantation (ASCT) has not

been well established in patients with WM. Several reasons can ac-count for that: the high median age of patients, the high variability in

overall survival (OS) between different subgroups of patients, and the

increasing number of newtherapeutic optionsmay allplaya role.Fewstudies with limited numbers of patients support the concept of a

dose-response effect in WM and confirm that ASCT may induce

long-term responses, even in heavily pretreated patients.13,14

In this retrospective analysis, we present the long-term outcome

of a group of 158 patients with advanced-stage WM treated with an

ASCT and reported to the European Group for Blood and MarrowTransplantation (EBMT) registry. To the best of our knowledge, this

series is the largest one published to date.

PATIENTS AND METHODS

Participating EBMT centers submitted data from patients with confirmeddiagnosis of WM as defined by WHO classification15 who were undergoingASCT. Patients were treated according to local protocols. Informed consentwas obtained locally according to regulations applicable at the time of trans-

plantation. As of January 2003,written informed consent was required beforedata registration. From theinitial cohortof 202 eligible patients with WM,thefinal analysis was performed in a group of 158 patients who had minimumclinical data. Survival and transplantation data were available for the wholegroup, but for 44 patients, diagnostic information was not available. A com-parison was performed between patients with and without missing values toensure that the exclusion of those 44 patients with no required information atdiagnosis did not introduce a bias in the final analysis.

Seventy-eight EBMT centers contributed data on 158 WM patients whoreceived a first ASCT between January 1991 andDecember 2005.The medianage at diagnosis was 49 years (range, 20 to 67 years), with 37% of the patientspresenting with intermediate-risk disease and 54% with high-risk disease asdefined by the WM InternationalPrognostic Scoring System (IPSS).16 Thirty-four percent of the patients presented with B symptoms, 30% with elevatedlactate dehydrogenase, 47% with anemia (hemoglobin 11.5 g/dL), 8.3%with thrombocytopenia (platelet count 100 109/L), 26% with low albu-min ( 35 g/L), 10.3% with IgM levels of 7.0 g/L, and 31% with elevated2-microglobulin levels ( 3.5 mg/L).

DefinitionsDisease response was evaluated on the basis of the Third International

WM Workshop recommendations.17 Immunofixation (IF) was not a stan-dard practice test for assessment of minimal residual disease in many centersuntil 2003. Therefore, response was defined as very good partial response(VGPR) if serum electrophoresis was negative but the results from IF werenotavailable. Chemosensitivity wasdefined by theachievementof a partialremission (PR) or a complete remission (CR) with the chemotherapy regi-men administered immediately preceding ASCT, whereas chemorefractorydisease included primary refractory disease or refractory relapse beforetransplantation. Patients who had at least 25% increase of monoclonalprotein from the lowestvalue or reappearance of cytopenia,lymphadenop-athy, or organomegaly were rated as progressive disease. Response to ASCTwas firstassessed at 100days post-transplantation and monitoredonce every 3months afterward.

Statistical AnalysisThe primary end points of the study were progression-free survival

(PFS), disease relapse or progression, nonrelapse mortality (NRM), and OS.The incidence of secondary malignancies was also investigated. PFS was de-fined as thetime from transplantationto relapse, progressive disease,or deathfrom any cause. NRM was defined as death from anycause other than diseaserelapseor progressionat anytimeafter ASCT.OS wasdefinedas thetimefromtransplantation to death from any cause; surviving patients were censored atlast follow-up.

The probabilities of OS and PFS were estimated from the time of trans-plantation using the Kaplan-Meier product-limit estimate18 and were com-pared by the log-rank test. Estimates of engraftment, NRM, relapse orprogression, and secondary malignancies were calculated using cumulativeincidence rates to accommodate competing risks and were compared by Coxunivariateanalysis.Potential prognostic factors for OS, PFS,relapse rate (RR),and NRM were evaluated in multivariate analyses by using Cox proportionalhazards regression. Some risk factors in the Cox model contained a categorycalled unknown to avoid loss of information. Backward stepwise variable

selectionat a significance level of 0.1 was used to identify covariates associatedwith the main outcomes. In each model, the assumption of proportionalhazards was tested for each variable by using a time-dependent covariate. Allvariables satisfied the proportionality assumption. A landmark approach wasused to investigate the impact of achieving a negative IF after ASCT on theoutcome. Cumulative incidences were calculated using NCSS97 software(NCSS, Kaysville,UT). All othercomputationswere performed usingthe SPSS13.0 statistical package (SPSS, Chicago, IL). All Pvalues were two-sided. Toensure that the selected patients were representative of all registered patients,outcomes were compared between the patients included and those excludedfrom the study19; no differences were noted.

RESULTS

Patient Characteristics at Transplantation

Characteristics of patients who underwent the ASCT procedure

are described in Table 1. Median age at transplantation was 53 years

(range,21 to 70 years). Thirty-four patients(21%) were autograftedinfirst VGPR (VGPR1), 14 (9%) in second VGPR (VGPR2), and eight

(5%) in the thirdor later VGPR (VGPR3). Forty-nine patients (31%)

were autografted in first partial response (PR1) and 30 (19%) in thesecond or later PR (PR2). Twelve patients (8%) were autografted in

chemosensitive relapse and the remaining 11 (7%) in chemorefrac-

tory disease. Granulocyte colony-stimulating factor (G-CSF) alonewasusedas mobilizationtherapyin 23%and chemotherapyG-CSF

in 77%, the latter being cyclophosphamide G-CSF in 60% of the

patients. Seventy percent of the patients had an adequate harvestfollowing one mobilization attempt, while 28% of the patients re-

quired two, and 2% had three mobilization attempts. Conditioning

regimen for transplantation was total-body irradiationbased in 45patients (28%) and chemotherapy-based in the remaining 113 pa-

tients (72%). Median follow-up of the surviving patientswas 4.2years

(range, 0.5 to 14.8 years).

Disease Response to Transplantation and Outcome

Responseafter ASCT could be evaluated in 155patients. Thebestresponse achieved at any time after ASCT was CR in 34 patients

(22%), VGPR in 77 patients (50%), or PR in 23 patients (15%).

Eighteen patients (11%) had disease relapse or progression, and in

three patients, the best response was not available. Best response afterASCT was achieved at a median time of 3 months (range, 1 to 24

months). Thirteen patients with VGPR and 21 with chemosensitivedisease at ASCT upgraded their response to CR after ASCT, while 36

patients with chemosensitive disease, two with chemorefractory dis-

ease, and 39 with VGPR achieved or maintained a VGPR (Table 2).Witha medianfollow-up of4.2 years(range, 0.5 to14.8years)for

the surviving patients, 107 patients (68%) are alive and 51 patients

(32%) have died, 42 (26%) of disease progression. Nine patients diedwithout disease progression, leading to a cumulative incidence of

NRM of 3.8% (95% CI, 1.7% to 8.4%) at 1 and 2 years post-ASCT,4.6% (95% CI, 2.2% to 9.5%) at 3 years post-ASCT, and 5.6% (95%

Kyriakou et al

2228 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



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CI, 2.8% to 11%) at 5 years post-ASCT (Fig 1A). Six patients died of

infections, two of multiorgan failure, and oneof cardiac toxicity. Onepatient died of progression to amyloidosis, one of small-cell lung

cancer, andtwoof acutemyeloidleukemia (AML) at 5, 0.5, 3.8, and4

years post-ASCT, respectively. Ten patients (6.3%) developed a sec-

ondary malignancy (SM)after ASCT (oneAML, four myelodysplastic

syndrome MDS, onemelanoma, oneprostatecarcinoma,one small-

cell lung cancer, and two other solid tumors) leading to a cumulativeincidence of SM of 8.4% (95% CI, 4.4% to 16.3%) at 5 years (Fig 1B).

Forthreeofthesepatients,theSMwasreportedtobethemaincauseof

death. Univariate analysis for the development of SM indicated thattheprioruse offludarabine(RR, 8.8;95%CI, 1.4 to53.6; P .017)was

the only prognostic factor. More than one mobilization attempt and

male sexwere associated with a trend to more SM afterASCT. A prioruse of fludarabine was the only independent prognostic factor for a

higher incidence of SM in the multivariate analysis (RR, 9.4; 95% CI,1.5 to 56.9; P .017).

TheestimatedOSratesat3and5yearswere77.6%(95%CI,71%to 84%) and 68.5% (95% CI, 60% to 77%), respectively (Fig 1C).Seventy-eight patients (49%) were alive and remained progression

free, with estimated PFS rates of 61.7% (95% CI, 54% to 70%) and

39.7% (95% CI, 31% to 50%) at 3 and 5 years, respectively (Fig 1C).Seventy-one patients (45%) have relapsed or progressed, with a me-

dian time from transplantation of 1.3 years (range, 0.1 to 5.1 years)

and estimated relapse rates of 33.7% (95% CI, 27% to 42%) and53.8% (95% CI, 44% to 62%) at 3 and 5 years, respectively (Fig 1A).

In 53 (48%) of 111 patients who achieved a CR or a VGPR,

information on IF was available after transplantation (34 IF-positiveand 19 IF-negative). A landmark analysis approach indicated that

those patients who achieved a negative IF within the first 6 months

after transplantation had a trend for a superior PFS (71% v29% at 5years; P .08) compared with those who were still IF-positive after

transplantation(Fig 2A). Nodifferenceswereseenintheprobabilityof

OS (86% v72%; not significant) between those who wereIF-negativeor IF-positive after transplantation (Fig 2B).

Prognostic Factors for NRM, RR, PFS, and OS

To ascertain which factors may have significantly influencedoutcome, both univariate and multivariate Cox regression analyses

were performed (Table 3). Chemorefractory disease and a poor per-

formance status at ASCT were associated with a higher NRM inunivariate analysis (P .004 and P .001, respectively). These two

Table 1. Patient Characteristics at Transplantation

CharacteristicNo.

AvailableNo. of

Patients %

Male sex 158 99 63

Age at diagnosis, years 158

Median 49

Range 20-67

50 74 47

60 10 6

65 2 1

No. of prior therapies 153

3 104 68

3 49 32

Interval diagnosis ASCT, months 158

Median 20

Range 3-244

2 88 56

2-3 36 23

3 34 21

Age at ASCT, years 158

Median 53

Range 21-70

50 98 62 60 24 15

65 8 5

Disease status at ASCT 158

VGPR1 34 22

VGPR2 14 9

At least VGPR3 8 5

PR1 49 31

At least PR2 30 19

Sensitive relapse 12 7

Refractory disease 11 7

Disease sensitivity at ASCT 158

Chemosensitive disease 147 93

Chemorefractory disease 11 7

Karnofsky status 80% at ASCT 117 113 97

Stem cell source 158

PB 148 94

BM 7 4

PB BM 3 2

CD34 cells infused in PB-ASCT 106 /kg 12.5

Median 3.9

Range 1-25.2

Conditioning regimen 158

TBI based 45 28

Chemotherapy based 113 72

BEAM protocol 73 46

Follow-up for surviving patients,years 13.2

Median 4.2

Range 0.5-14.8

Abbreviations: ASCT, autologous stem-cell transplantation; VGPR, very goodpartial response; VGPR1, first VGPR; VGPR2, second VGPR; VGPR3, third orlater VGPR; PR, partial response; PB, peripheral blood; BM, bone marrow; TBI,total body irradiation; BEAM (carmustine, etoposide, cytarabine, melphalan).

Table 2. Post-Transplantation Outcome by Disease Status at the Timeof ASCT

Outcome

Disease Status at ASCT

TotalVGPR1

AtLeast

VGPR2Chemosensitive

DiseaseChemorefractory

Disease

CR 10 3 21 0 34

VGPR 20 19 36 2 77

PR 0 0 18 5 23

No response(SD,progression) 4 0 11 3 18

N/E 0 0 2 1 3

N/A 0 0 3 0 3

Total 34 22 91 11 158

Abbreviations: ASCT, autologous stem-cell transplantation; VGPR, very goodpartial response; VGPR1, first VGPR; VGPR2, second VGPR; CR, completeremission; PR, partial remission; SD, stable disease; N/E, not evaluable; N/A,not available.

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covariates were strongly related; only four patients had poor perfor-

mance at ASCT, three of themwith chemorefractory disease. Looking

at thepatientswithout poorperformancestatus, no statistically signif-icant independent prognostic factors could be identified for NRM in

the multivariate analysis, but chemorefractory disease showed a trend

to a higher NRM (P .1). Having received at least three treatmentlines before ASCT and having chemorefractory disease at ASCT were

adverse prognostic factors in univariate analysis for RR after ASCT.

Both factors, chemorefractory disease at thetime of ASCT (P .003)

and having received at least three treatment lines (P .001) were

associated with an increased RR after transplantation in multivariate

analyses. Heavily pretreated patients, patients with refractory disease,and those with poor performance status had shorter PFS and OS in

univariate analysis. In multivariate analyses, chemorefractory disease

at ASCT (P .001) and at least three treatment lines (P .001) werethe most important independent prognostic factors for a significantly

shorter PFS. Three or more treatment lines (P .001), chemorefrac-

tory disease at ASCT (P .03), male sex(P .04), andage 50 years

(P .05) were associated with a significantly inferior OS.A subgroupanalysis was performed on patientsautograftedafter

a first response (VGPR1/PR1). There were 69 such patients (medianageof 50yearsat ASCT). Median time from diagnosis toASCT was10

months (range, 3.5 to 41 months). Fifty percent presented with ane-

mia and 14% with a low platelet count. In 8% of the patients, IgMwas 70 g/dL, and in 22%, albumin was 35 g/dL. Thirty patients

were autografted in VGPR1 and 39 in PR1. With a median follow-up

for the surviving patients of 4.5 years (range, 0.5 to 14.8 years), esti-matedPFSat3and5yearswas73%(95%CI,62%to84%)and51.5%

(95% CI, 37% to 66%), respectively (Fig 3). Estimated OS at 3 and 5years was 84% (95% CI, 75% to 92%) and 77% (95% CI, 66% to

A

CumulativeIncidence

(p

roportion)

Time Since ASCT (years)

1.0

0.8

0.6

0.4

0.2

0 1 2 3

Relapse or progression

NRM

4 5 6 7 8

B

CumulativeInc

idenceof

SecondMalignanc

y(proportion)


1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10

Overall survival

PFS

8.4%

C

ProbabilityofSu

rvival

1.0

0.8

0.6

0.4

0.2

0 1 2 3 4 5 6 7 8


Fig 1. (A) Cumulative incidence of relapse or progression and nonrelapse

mortality (NRM). (B) Cumulative incidence of secondary malignancies. (C) Kaplan-

Meier plot of progression-free survival (PFS) and overall survival probabilities.ASCT, autologous stem-cell transplantation.

A

Progression-FreeSurvival

(pro

portion)


1.0

0.8

0.6

0.4

0.2

0 1 2 3

-IF (n = 33)

+ IF (n = 18)

P= .08

4 5 6 7 8

Landmark: 6 months

B

OverallSu

rvival

(propor

tion)


1.0

0.8

0.6

0.4

0.2

0 1 2 3

-IF (n = 33)

+ IF (n = 18)

n.s.

4 5 6 7 8

Landmark: 6 months

Fig 2. (A) Progression-free survival (PFS) by immunofixation (IF) after autologous

stem-cell transplantation (ASCT); analysis restricted to patients achieving a very good

partial response after ASCT. Landmark analysis: Probability of PFS was estimated

from 6 months after ASCT according to the IF status. (B) Overall survival by IF after

ASCT; analysis restricted to patients achieving a very good partial response after

ASCT. Landmark analysis: Probability of overall survival was estimated from 6months after ASCT according to the IF status. n.s., not significant.

Kyriakou et al




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88%), respectively (Fig 3). No differences in the probability of PFS orOS were observed between patients in VGPR1 or PR1.

DISCUSSION

Whether ASCT has an important role in the management of WMremains to be determined. The older median age of the patients, the

difficulty inidentifyingadverseprognosticfactors at diagnosis, andthe

recent development of new drugs for treating this disease have allcontributed to this fact. The recently published IPSS for WM16 sepa-

rates a group of good-prognosis patients with a median survival of 12

years in whom optimal treatment should avoid toxicity and preserve

qualityof life froma group of high-risk patientswith a mediansurvivalof only 3 years in whom innovative approaches are required.

The previous reported information on ASCT and WM comesfrom series with relativelylownumbers of patients. TheFrench expe-

rience comprises 19 heavily pretreated patients who showed NRM of

6% and PFS of 45% with a follow-up of 0.8 to 2.8 years.20 The Centerfor International Blood and Marrow Transplant Research(CIBMTR)

reported 10patients who had NRM of 11% and PFS of 78% and 65%

at 1 and3 years, respectively.13 In an updated report from Dreger andSchmitz14 on a group of 12 patients with symptomatic disease that

were autografted after first-line therapy, all patients were alive and six

of them were free of disease with a median follow-up of 5.8 years.Altogether, these reports indicated that ASCT can achieve long-term

remissions in patientswith poor-prognosis disease;the lownumberof

patients, however, did not allow a meaningful conclusion regardinghowmanypatientswillbenefitfromASCTandwhichriskfactorsneed

to be considered.

In this much larger series, NRM is low (3.8% at 1 year, 5.6% at 5years) confirming what had previously been reported.14,17,20 Ten pa-

tients died later after transplantation because of SM, resulting in a

cumulative incidence of 8.6% at 5 years. Of note, a recent reportdemonstratedan increasedincidence oftransformationtoMDS/AML

in WM patients treated with nucleoside analogs.21 Of 439 patients

with WM193 were treated with nucleoside analog and 136 were

not12 patients from the nucleoside analog group developed MDS/AML compared with one patient in the non-nucleoside-analogtreated group (P .001). In our series, five patients developed MDS/

AML after ASCT. Analysis of independent prognostic factors for the

development of this fatal complication revealed that the administra-tion of fludarabine before ASCT was the only adverse prognostic

factor. Of interest, theunivariateanalysis identified theneed formore

than one mobilization attempt, a surrogate marker for hematopoieticreserve and stem-cell quality, as a predictive factor for the develop-

ment of SM.

ASCT resulted ina high number of CRs andVGPRs. WhileCRisrarewith conventionaltherapiesand nothigher than5%, inthisstudy,

we report 22% CRs and 50% VGPRs. With a long median follow-up

for the surviving patients of 4.2 years, the projected 5-years PFS andOS for the whole series were 41% and 68%, respectively. These per-

centagesare inagreement withwhat hasbeenpublishedpreviously.As

expected, patients autografted in refractory disease and those whowere heavily pretreated had the worst outcome in terms of both PFS

and OS. RR after ASCT was extremely high 50% at 5 years after

transplantation overall and even higher in chemorefractory patientsandthose receiving atleastthree lines oftherapy.It seemsclear that the

patients with chemosensitive, good-prognosis disease, transplanted

early in the course of the disease benefited more from the ASCT. Foryounger patients with WM, ASCT represents another positive alter-

native therapeutic option. We analyzed the results of ASCT in 69

patientsautografted after a firstresponsewas achieved. Thirty percent

of thepatientshad twoadverseprognostic factors.16Five-year PFSandOS were 51.5% and 77% with what seems to be a plateau in terms of

PFS after the first 5 years following transplantation. These results arehighly encouraging, taking into account that a proportion of these

patients displayed poor prognostic features at the time of diagnosis.

Becausethetoxicity of theprocedure in such patientsis rather limited,ASCT represents a reasonable option in WM patients with high-risk

or early-relapse disease.

Although thenumberof patientswith available IFdatawas small,a landmark approach showed that achievement of a negative IF after

ASCT wasassociatedwitha better(butnot statistically significant)PFS

with no differences inOS. This findingneeds to beconfirmed inlarger

Table 3. Adverse Prognostic Factors for Post-Transplantation Outcome inMultivariate Analyses

Adverse Prognostic FactorRelative

Risk 95% CI P

Relapse progression

At least three prior lines of therapy 2.5 1.5 to 4.1 .001

Refractory disease at ASCT 3.9 1.6 to 9.4 .003

Progression-free survival



Overall survival

Male sex 2.0 1.1 to 3.9 .04


Age at ASCT 50 years 1.9 1.0 to 3.8 .05


NOTE. Covariates included in the Cox models: year of autologous stem-celltransplantation (ASCT), sex, age, time from diagnosis to ASCT, number ofprior treatment lines, disease status at ASCT, and the type of conditioningregimen. Covariates with a P value .05 are included.

Probabilityo

fSurvival


0.8

0.6

0.4

0.2

0 1 2 3

Overall survival

PFS

4 5 6 7 8

1.0

Fig 3. Kaplan-Meier plot of progression-free survival (PFS) and overall survival

for patients who received autologous stem-cell transplantation (ASCT) in first

very good partial response and first partial response.

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prospectivestudies,but it highlightstheimportanceof achieving min-

imal residual disease in WM as has been well described in otherdiseases such as multiple myeloma.22

In summary, this analysis represents the largest experience pub-

lished to date of the long-term outcome of ASCT in a selected popu-lation of young but heavily pretreated WM patients. Toxicity of the

procedure is acceptable, and long-term outcome for those patients

autograftedin early stagesisencouraging.Prospectivestudiesintegrat-ingearly ASCTintothetreatmentalgorithmfor patients withWMare

warranted. ASCT should be considered as a therapeutic option in

young patients with advanced WM. ASCT should not be offered topatients with chemoresistant disease or to those who have received

more than three lines of therapy.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Charalampia Kyriakou

Provision of study materials or patients: Charalampia Kyriakou, David

Sibon, Jean Yves Cahn, Majid Kazmi, William Arcese, Karin Kolbe, Norbert

Claude Gorin, Kristy Thomson, Noel Milpied, Dietger Niederwieser, Karel

Indrak, Paolo Corradini, Anna Sureda, Norbert Schmitz

Collection and assembly of data:Charalampia Kyriakou, Carmen Canals,David Sibon, Jean Yves Cahn, Majid Kazmi, William Arcese, Karin Kolbe,

Norbert Claude Gorin, Kristy Thomson, Noel Milpied, Dietger

Niederwieser, Karel Indrak, Paolo Corradini, Anna Sureda, Norbert Schmitz

Data analysis and interpretation: Charalampia Kyriakou, Carmen

Canals, Anna Sureda, Norbert Schmitz

Manuscript writing: Charalampia Kyriakou, Anna Sureda,

Norbert Schmitz

Final approval of manuscript: Charalampia Kyriakou, Carmen Canals,

David Sibon, Jean Yves Cahn, Majid Kazmi, William Arcese, Karin Kolbe,

Norbert Claude Gorin, Kristy Thomson, Noel Milpied, Dietger

Niederwieser, Karel Indrak, Paolo Corradini, Anna Sureda, Norbert Schmitz

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Terapia de alta dose e transplante autólogo de células-tronco na Macroglobulinemia de Waldenström

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