Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell

originalreport

Graft-Versus-Leukemia Effectof Allogeneic Stem-CellTransplantation and MinimalResidual Disease in Patients WithAcute Myeloid Leukemia in FirstComplete Remission

abstract

Purpose The detection of minimal residual disease (MRD) in patients with acute myeloidleukemia (AML) may improve future risk-adapted treatment strategies. We assessed whetherMRD-positive andMRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT).

MethodsA total of 1,511patientswere treated in subsequentDutch-BelgianHemato-OncologyCooperativeGroup and the SwissGroup forClinical Cancer Research AML trials, of whom547obtained a first complete remission, received postremission treatment (PRT), and had availableflow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with aleukemia-associated immunophenotype within the WBC compartment. PRT consisted ofalloHSCT(n=282), conventionalPRTby a third cycle of chemotherapy (n=160), or autologoushematopoietic stem-cell transplantation (n = 105).

Results MRD was positive in 129 patients (24%) after induction chemotherapy before pro-ceeding to PRT. Overall survival and relapse-free survival were significantly better in patientswithoutMRD before PRT compared withMRD-positive patients (65%6 2% v 50%6 5% at 4years;P= .002; and58%63% v38%64%;P< .001, respectively), whichwasmainly becauseof alower cumulative incidence of relapse (32% 6 2% compared with 54% 6 4%; P < .001, re-spectively). Multivariable analysis with adjustment for covariables showed that the incidence ofrelapse was significantly reduced after alloHSCT compared with chemotherapy or autologoushematopoietic stem cell transplantation (hazard ratio [HR], 0.36; P < .001), which was similarlyexerted in both MRD-negative and MRD-positive patients (HR, 0.38; P < .001; and HR, 0.35;P < .001, respectively).

Conclusion The graft-versus-leukemia effect of alloHSCT is equally present in MRD-positiveand MRD-negative patients, which advocates a personalized application of alloHSCT, takinginto account the risk of relapse determined by AML risk group and MRD status, as well as thecounterbalancing risk of nonrelapse mortality.

Precis Oncol 00. © 2017 by American Society of Clinical Oncology

INTRODUCTION

Acute myeloid leukemia (AML) is a heterogeneousmalignancy characterized by a varietyof underlyingcytogenetic and molecular aberrations, which areassociated with distinct prognostic features.1 Al-though current treatment approaches induce high

percentages of hematologic remission, relapse ratesare high and vary according to the underlying riskprofile.2 Recently, the European LeukemiaNet(ELN) developed an updated classification on thebasis of cytogenetic and molecular aberrancies dis-tinguishing patients with a favorable, intermediate,

Jurjen Versluis

Burak Kalin

Wendelien Zeijlemaker

Jakob Passweg

Carlos Graux

Markus G. Manz

Marie-ChristianeVekemans

Bart J. Biemond

Marie-Cecile J.C.Legdeur

Marinus van MarwijkKooy

Okke de Weerdt

Pierre W. Wijermans

Mels Hoogendoorn

Mario J. Bargetzi

Juergen Kuball

Harry C. Schouten

Vincent H.J. van derVelden

Jeroen J.W.M. Janssen

Thomas Pabst

Bob Lowenberg

Mojca Jongen-Lavrencic

Gerrit Jan Schuurhuis

(continued)

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or adverse treatment response.3 Postremissiontreatment (PRT) decisions are currently tai-lored according to AML risk groups, wherebyallogeneic hematopoietic stem-cell transplan-tation (alloHSCT) is generally not used inpatients with favorable-risk AML, but is gen-erally highly recommended in patients withadverse-risk AML.3-6 AML risk classificationmay be further improved by introducing theassessment of minimal residual disease (MRD)early after induction chemotherapy, but alsoafter PRT.7-24 Assessment of MRD after in-duction treatment for specificmarkers by eithermultiparametric flow cytometry or quantitativepolymerase chain reaction has firmly been showntopredict relapse andoverall outcome, regardlessof the type of PRT.10-24 Consequently, MRDnegativity was introduced as a clinical end pointin patients with a hematologic complete remis-sion (CR).3 Despite PRTwith alloHSCT, a two-to five-fold increased incidence of relapse inMRD-positive patients was observed comparedwith MRD-negative patients,17-24 which raisesthe question of whether and to what extentMRD-positive patients may benefit from thegraft-versus-leukemia (GVL) effect of alloHSCT.Conversely, the low relapse rate in MRD-negativealloHSCT recipients also evokes the question ofwhether GVL is operational in that subgroupand to what extent it may be blunted by non-relapse mortality (NRM). Therefore, we eval-uated whether and to what extent alloHSCTquantitatively reduces relapse compared withconventional PRT in upfront-treated patientswith MRD-positive or MRD-negative AML infirst CR (CR1).

METHODS

Patients

Patients participated in three prospective, consec-utive Dutch-BelgianHemato-Oncology Cooper-ative Group and the Swiss Group for ClinicalCancer Research (HOVON-SAKK) collaborativegroup trials (AML42, AML92, and AML102; theNetherlands Trial Register numbers NTR230,NTR1446,andNRT2187,respectively), forwhomassessment of MRD after induction therapy andbefore PRT by alloHSCT, chemotherapy, or au-tologous HSCT (autoHSCT) was performed.25,26

The results of the AML92 trial have not yet beenpublished, but trial information is available in theNetherlands Trial Register (NTR1446). A total of1,511 newly diagnosed patients with AML wereincluded for whom treatment was started between2006 and 2014. Patients were excluded if CR1 didnot occur after two induction cycles of chemother-apy (n = 255; 17%) or the patient did not receivePRT after obtaining CR1 (n = 234; 15%). Inaddition, a total of 475 patients (31%) receivedPRT in CR1; however, their MRD status wasnot available within a time window of 4 monthsbefore PRT. A total of 547 patients with availableMRD status who received PRT inCR1were avail-able for analysis (Fig 1). Patients were classified byAMLprognostic riskonthebasis of the cytogeneticand molecular profile of the underlying AML,according to the ELN2017 risk classification.3

Molecular analysis was available for the majorityof patients, specifically for NPM1 (93%); fms-liketyrosine kinase 3 internal tandem duplication(FLT3-ITD; 91%), including the FLT3-ITDmu-tant to wild-type ratio (86%); EVI1 (79%);ASXL1(83%); RUNX1 (47%); and TP53 (47%). Patientsfor whom molecular analyses were not availablewere considered as not having the mutation incalculating the ELN2017 risk classification. Allstudies were approved by the ethics committeesof participating institutions and were conducted inaccordance with the Declaration of Helsinki. Allparticipants gave written informed consent. A de-tailed description of the inclusion and exclusioncriteria of the studies can be found in the DataSupplement.

Treatment Protocols

Treatment in the HOVON-SAKK AML42A,AML92, and AML102 trials involved a maximumof two remission induction cycles consistingof a first course of idarubicin with cytarabineand a second cycle of high-dose cytarabine withamsacrine, as previously described.25,26 Patientswere randomly assigned to granulocyte-colony

Assessed for eligibility HOVON-SAKK AML42A HOVON-SAKK AML92 HOVON-SAKK AML102

(N = 1,511)(n = 511)(n = 142)(n = 858)

Patients eligible for analysis(n = 547)

MRD negative CT Auto Allo

(n = 418)(n = 118)(n = 89)

(n = 211)

MRD positive CT Auto Allo

(n = 129)(n = 42)(n = 16)(n = 71)

Excluded Obtained no CR Received no PRT No available MRD

(n = 964)(n = 255)(n = 234)(n = 475)

Gert Ossenkoppele

Jan J. Cornelissen

Author affiliations andsupport information (ifapplicable) appear at theend of this article.J.V. and B.K. contributedequally to this work.Corresponding author:Jan J. Cornelissen, MD,PhD, Department ofHematology, ErasmusUniversity Medical CenterCancer Institute, GroeneHilledijk 301, 3075 EA,Rotterdam, theNetherlands; e-mail:[email protected].

Fig 1. CONSORTdiagram. Abbreviations:AML, acute myeloidleukemia; allo, allogeneichematopoietic stem-celltransplantation; auto,autologous hematopoieticstem-cell transplantation;CR, complete remission,CT, chemotherapy;HOVON-SAKK, Dutch-BelgianHemato-OncologyCooperativeGroup and theSwiss Group for ClinicalCancer Research; MRD,minimal residual disease;PRT, postremissiontreatment.

2 ascopubs.org/journal/po JCO™ Precision Oncology


mailto:[email protected]

mailto:[email protected]


stimulating factor (AML42A), laromustine(AML92), and clofarabine (AML102). Afterobtaining CR1, patients subsequently receivedPRT to a predefined strategy as outlined in thestudy protocols, but without knowledge of thepatients’MRD status. PRT included a third cycleof chemotherapy with mitoxantrone and etopo-side, high-dose chemotherapy with busulfan andcyclophosphamide followed by autoHSCT, oralloHSCT after either myeloablative condition-ing or reduced intensity conditioning (RIC). Themyeloablative conditioning regimen containedhigh-dose cyclophosphamide with at least 8 Gytotal body irradiation (TBI) in 83 patients (76%);the remainder of the patients received busulfanwith cyclophosphamide. Although RIC regimensvaried, the majority contained low-dose (2 or4 Gy) TBI preceded by fludarabine (n = 126;77%), whereas 23% of the patients received flu-darabine with busulfan. These different PRTmodalities were applied according to a risk-adapted strategy: patients with AML classifiedas favorable risk, according to cytogenetic andmolecular analysis, were planned for a third cycleof chemotherapy; intermediate-risk patients werepreferentially treated with alloHSCT using anHLA-matched sibling donor or a fully HLA-matched unrelated donor, if available; patientswith adverse-risk AML proceeded to alloHSCTusing a sibling donor, an unrelated donor, or cordblood grafts; and patients alternatively receivedautoHSCT or a third cycle of chemotherapy if nosuitable donor was available.25-28

MRD Detection and Sample Selection

MRD flow cytometric analysis was performed in atwo-step procedure, as previously described.18 Insummary, the immunophenotypewas determinedon blasts defined by CD45 expression with a lowsideward scatter. The leukemia-associated immu-nophenotype (LAIP)atdiagnosiswas identifiedbydetecting aberrantly expressed markers/markercombinations to distinguish leukemic blasts fromnormal hematopoietic progenitor cells. Bonemarrow samples were collected at diagnosis todetermine LAIP and follow-up after each chemo-therapy cycle. The sensitivity of flow cytometrycould lead to detection of one leukemic cell in1,000, up to100,000WBCs.MRDpercentagewasdefined as the percentage of LAIP cells within theWBC compartment multiplied by the correctionfactor (100% divided by the percentage of LAIP-positive blasts at diagnosis). A percentage above0.1% was considered MRD-positive, as validatedinprevious studies.18MRDsamples obtainedaftercycle 2 in patients with AML in CR1 were used,

Table 1. Patient Characteristics

Characteristic

MRD Negative(n = 418)

MRD Positive(n = 129)

No. % No. %

Sex P = .129

Male 207 50 70 54

Female 211 50 59 46

Age, years P = .099

Median 51 49

Range 18-65 18-65

WBC count at diagnosis, 109/l P = .049

< 100 389 93 113 88

. 100 29 7 16 12

Cytogenetics of AML P = .008

t(8;21) 25 6 7 5

inv(16) 15 4 15 12

CN-X-Y 220 53 56 43

Cytogenetic abnormalities 110 26 36 28

Monosomal karyotype 30 7 12 9

Missing 18 4 3 2

NPM1 mutation -P = .001

No 238 57 91 71

Yes 151 36 27 21

Missing 29 7 11 9

FLT3-ITD* P = .87

Absent 289 69 86 67

Low ratio 75 18 24 19

High ratio 16 4 6 5

Missing 38 9 13 10

ELN2017 risk classification P = .20

Favorable 163 39 39 30

Intermediate 144 34 51 40

Adverse 111 27 39 30

CR reached after P = .003

Cycle 1 (early CR) 373 89 102 79

Cycle 2 (late CR) 45 11 27 21

Postremission treatment P = .079

Chemotherapy 118 28 42 33

Autologous HSCT 89 21 16 12

Allogeneic HSCT 211 50 71 55

Time from diagnosis to CR, days P = .084

Median 34 35

IQR 29-40 31-46

Time from CR to PRT, days P = .009

Median 74 65

IQR 56-96 48-90

(Continued on following page)

ascopubs.org/journal/po JCO™ Precision Oncology 3



with a maximum time from the MRD sample tosubsequent PRT of 4 months. The sample withthe shortest time interval between PRT and thedate of collection was selected for analysis.

End Points

The primary end point of the study was thecumulative incidence of relapse. Outcome esti-mates weremeasured from the date of starting thefirst PRT. Overall survival (OS) was based ondeath from any cause; patients were censored atthe date of last contact, if alive. The events forrelapse-free survival (RFS) were death in CR1,designated as NRM, or hematologic relapse. Thecumulative risks of relapse and NRM over timewere calculated as competing risks with actuarialmethods, where patients alive in continuing CR1were censored at the date of last contact.

Statistical Methods

A time-dependent analysis of PRTwas performedas described previously28,29 by applyingmultivari-able Cox regression with alloHSCT as the time-dependent covariable. The multivariable analysisis conceptually similar toaMantel-Byar analysis,30

but is more general because it allows for adjust-ment of other factors. A number of patients re-ceived PRT with chemotherapy (n = 44) firstbefore theyproceeded to alloHSCTincontinuingCR1. In both the multivariable analysis and theestimation of the survival curves, these patientswere counted as at risk in the chemotherapy groupfrom the start of PRT until alloHSCT and afterthat as at risk in the alloHSCT group. Forwardselection with the variables significantly associatedwith relapse after univariable analysis was used fordeveloping the multivariable model. MultivariableCox regression analysis for relapse, OS, RFS, andNRM was applied, stratified by the total numberof induction courses. Stratification by the total

number of induction courses (ie, I or II) was per-formed to allow the baseline hazard to differ be-tween these two patient groups. All P values werebased on log likelihood ratio tests, except whenexplicitly statedotherwise.Theproportionalhazardassumption was tested on the basis of Schoenfeldresiduals.30,31Pvalueswerenotadjustedformultipletesting. All analyses were performed with STATAsoftware (Release 13.1; STATA Corporation, Col-lege Station, TX).

RESULTS

Patient Characteristics

A total of 547 patients with AML in CR1 andavailable MRD status proceeded to PRT witheither alloHSCT (n = 282), chemotherapy(n = 160), or autoHSCT (n = 105). A total of129 patients (24%) were MRD positive afterinduction chemotherapy before proceeding tofirst PRT. Patient characteristics are listed inTable 1. Patients with mutatedNPM1 were morefrequentlyMRDnegative,whereasMRD-positivepatients more frequently tended to obtain a lateCR1 (ie, after induction cycle 2). The ELN2017risk classification was similarly distributed amongtheMRD-negative andMRD-positive patients.Interestingly, the time interval from CR1 toPRT for patients with MRD-positive AMLwas shorter compared with their negative coun-terparts, which was mainly apparent in favorable-risk patients with AML. The median follow-upof patients still alive was 50 months. Details ofthe characteristics of alloHSCT are listed inTable 2. No other differences with regard todonor source, conditioning, cytomegalovirusserostatus, and European Group for Blood andMarrow Transplantation (EBMT) risk score wereapparent between MRD-negative and MRD-positive patients. AlloHSCT recipients receiveda sibling donor in 50% of the transplantations,whereas 42% of patients underwent transplanta-tion with a matched unrelated donor. AlloHSCTwith RIC was predominantly performed, and con-ditioningmostly includedTBI.Patientswithahighrisk of NRM according to the EBMT risk score32

(> 3 points) represented 45% of the patients whounderwent transplantation.

Treatment Outcome

OS and RFS were significantly better in patientswithoutMRDbefore PRT comparedwithMRD-positive patients (65% 6 2% v 50% 6 5% at4 years; P = .002; and 58% 6 3% v 38% 6 4%;P, .001, respectively; Figs 2A and 2B). Improvedoutcomewasmainly caused by a lower cumulative

Table 1. Patient Characteristics (Continued)

Characteristic



No. % No. %

Year of PRT P = .11

Median 2011 2010

Range 2006-2014 2006-2014

Abbreviations: AML, acute myeloid leukemia; CN-X-Y, cytogenetically normal or only loss of X orY chromosome; CR, complete remission; ELN2017, European LeukemiaNet 2017; HSCT, hemato-poietic stem-cell transplantation; IQR, interquartile range; FLT3-ITD, fms-like tyrosine kinase 3internal tandem duplication; MRD, minimal residual disease; NPM1, nucleophosmin-1; PRT, post-remission treatment.*The cutoff of the FLT3-ITD ratio is defined as 0.50.




incidence of relapse in MRD-negative patientscompared with MRD-positive patients (32% 62% compared with 54% 6 4% at 4 years;P , .001, respectively; Fig 2C), whereas NRMwas not significantly different and estimated at 1061% (Fig 2D). More detailed outcome estimatesaccording to MRD status, type of PRT, and riskof NRM on the basis of the EBMT risk score arepresented in the Data Supplement.

The cumulative incidence of relapse was signifi-cantly lower in patients without MRD receiv-ing alloHSCT compared with chemotherapy orautoHSCT (26% 6 3% v 38% 6 3% at 4 years;

P = .027, respectively; Fig 3A). The cumulativeincidence of relapse in MRD-positive patients isestimated to be 45%6 6%comparedwith 66%66%at4years (P= .058) for recipients of alloHSCTcompared with recipients of chemotherapy orautoHSCT, respectively (Fig 3B). RFS afteralloHSCT proved similar compared with PRTwith chemotherapy or autoHSCT in patientswithout MRD before PRT (58% 6 4% v 58% 64% at 4 years; P = .99, respectively; Fig 3C). RFSafter alloHSCT in MRD-positive patients beforePRT was 44% 6 6% compared with 31% 66% at 4 years (P = .20) after chemotherapy orautoHSCT, respectively (Fig 3D). The type ofconditioning did not significantly affect the in-cidenceof relapseorRFS (DataSupplement).Thecumulative incidence of NRM after alloHSCTwas 15% 6 2% and was significantly affected bythe EBMT risk score (Data Supplement). NRMsplit by the EBMTrisk score showed lessNRM inpatients with a low EBMT risk score comparedwith patients with a high EBMT risk score (< 2compared with . 2); 10% 6 2% compared with22% 6 4%; P = .005, respectively.

A total of 208 patients developed a relapse afterhaving received PRT, of whom 120 (57%) pro-ceeded to salvage chemotherapy and 70 (59%)entered a secondCR.Only46of relapsingpatients(22%) proceeded to alloHSCT after obtaining asecond CR.

Multivariable Analysis

The following variables significantly predicted forrelapse in the univariable analysis: MRD status,type of PRT, age, WBC category, FLT3-ITDcategory, year of PRT, time from diagnosis toCR, time from CR to PRT, cytogenetics, num-ber of cycles to CR, ELN2017 risk classifica-tion, NPM1 mutation, EVI1 overexpression, andCEBPA doublemutation. After forward selection,the multivariable analysis was performed, strati-fied by the total number of induction courseswith adjustment for MRD status, type of PRT,age, WBC category at diagnosis, FLT3-ITD,ELN2017 risk classification, number of cycles toCR, and year of PRT (Table 3). Relapse of AMLwas significantly reduced after alloHSCT com-pared with chemotherapy or autoHSCT (HR,0.36; P , .001). This hazard ratio quantifies theallogeneic GVL-effect of alloHSCT. That GVL-effect was similarly exerted in MRD-negative andMRD-positive patients (HR, 0.38; P , .001; andHR, 0.35; P, .001; Fig 4A), which was also sim-ilar comparing alloHSCTwith chemotherapy oralloHSCT with autoHSCT (Data Supplement).

Table 2. Transplantation Characteristics

Characteristic



No. % No. %

Donor source P = .29

HLA-identical sibling 107 51 35 49

Matched unrelated donor 90 43 29 41

Umbilical cord blood 7 3 6 8

Other 7 3 1 1

Conditioning P = .85

Myeloablative cyclophosphamide plus TBI 63 30 20 28

Cyclophosphamide plus busulfan 20 9 6 8

Reduced-intensity fludarabine plus TBI 89 42 31 44

Fludarabine plus busulfan 24 11 11 15

Unknown 15 7 3 4

Stem cell source P = .13

Bone marrow 10 5 4 6

Peripheral blood 186 88 59 83

Cord blood 6 3 6 8

Missing 9 4 2 3

CMV serostatus patient/donor P = .059

Negative/negative 25 12 3 4

Other 108 51 41 58

Missing 78 37 27 38

Female donor to male recipient P = .89

No 168 80 56 79

Yes 43 20 15 21

EBMT risk score P = .40

0 0 1 1

1 26 12 9 13

2 93 44 26 37

3 81 38 31 44

4 11 5 4 6

Abbreviations: CMV, cytomegalovirus; EBMT, European Group for Blood and Marrow Transplan-tation; MRD, minimal residual disease; TBI, total-body irradiation.




Despite significantly increased NRM (HR, 2.94;P = .003), RFS was better after alloHSCT com-pared with chemotherapy or autoHSCT (HR,0.53;P, .001,Fig4B;DataSupplement),whereasOS was not significantly different (Table 3). Dif-ferent variables in the multivariable model weresignificantly associated with relapse, with theELN2017 risk classification, FLT3-ITD mutantto wild-type ratio, number of cycles to reach CR,and type of PRT being the most importantvariables.

DISCUSSION

The development of treatment approaches inpatients with AML is increasingly personalizedby using genetic and molecular leukemia charac-teristics at diagnosis and individual treatmentresponse.3-6 Response and especially MRD, de-tected by either multiparametric flow cytometryor quantitative polymerase chain reaction, hasbecome an important parameter in amore precisetreatment approach for patients with AML.10-24

Currently, it is unknown whether and how the

presence or absence of MRD should guide theapplication of alloHSCT as PRT. Recently, thequantitative detection ofmutatedNPM1 has beenshown to have high predictive value, and recom-mendations to tailor the application of alloHSCTby MRD were made.10-12 Balsat et al10 suggestedrefraining from alloHSCT in NPM1 MRD-negative patients and to selectively proceed toalloHSCT as PRT in CR1 in MRD-positivepatients or adverse-risk patients on the basis ofkaryotype or the presence of FLT3-ITD. In ad-dition, Buccisano et al33 concluded in a recentanalysis that MRD-positive patients, as deter-mined by flow cytometry, could also benefit fromalloHSCT. Although it has been suggested thatoverall outcome is improved by alloHSCT inMRD-positive patients, it is still unknown towhatquantitative extent alloHSCT reduces relapse inMRD-positive patients and how that compareswith MRD-negative patients.

Here, we show that the allogeneic GVL effect—asestimated by the relative reduction of relapse—is similar in MRD-positive and MRD-negative

Negative

Positive

Cox LR P = .0020

No.

418

129

F

146

64

Negative

Positive

No. at risk:

418

129

334

86

280

64

216

56

151

45

Negative

Positive

25

50

75

100

OS (%

)

Time (months)0 12 24 36 48

Negative

Positive

Cox LR P < .0001

No.

418

129

F

138

70

Time (months)

Negative

Positive

No. at risk:

418

129

296

62

249

53

193

44

136

36

Negative

Positive

25

50

75

100

CI o

f Rel

apse

(%)

0 12 24 36 48

Negative

Positive

Cox LR P = .0001

No.

418

129

F

183

80

Time (months)

Negative

Positive

No. at risk:

418

129

296

62

249

53

193

44

136

36

Negative

Positive25

50

75

100

RFS

(%)

0 12 24 36 48

Negative

Positive

Cox LR P = .71

No.

418

129

F

45

10

Time (months)

Negative

Positive

No. at risk:

418

129

296

62

249

53

193

44

136

36

Negative

Positive

25

50

75

100

CI o

f NRM

(%)

0 12 24 36 48

A

C

B

D

Fig 2. Outcome byminimal residual disease(MRD) status. Kaplan-Meier estimates of (A)overall survival (OS), (B)relapse-free survival (RFS),(C) cumulative incidence(CI) of relapse, and (D) CIof nonrelapse mortality(NRM) by MRD status inpatients with acute myeloidleukemia in first completeremission from start ofpostremission treatment.Abbreviations: F, numberof failures (ie, deathwhatever the cause); LR,likelihood ratio; No.,number of patients.




patients, with a reduction of 63% by alloHSCTcompared with chemotherapy or autoHSCT.These results compare well with earlier findingsin cytogenetic subgroups, in which theGVL effectseemed to be similar among patients with a mono-somal karyotype, core binding factor AML, ornormal karyotype.34 These observations are mostreadily explained by the abundant expression ofclass I and II HLA antigens on malignant myeloidprecursor cells and their susceptibility to alloreac-tive T cells, includingT cells recognizingminor ormajorHLAantigens.35-37They suggest thatT-cellalloreactivity might exert antileukemic effects re-gardless of the underlying subcategory of AML,although absolute estimates of relapse incidence dodiffer and may rather reflect differences in diseasebiology, such as intrinsic resistance.

Although alloHSCT provides a strong GVL ef-fect, counterbalancing NRM may be of concern.Because NRM critically depends on a numberof different risk factors, it has become imperativeto assess the NRM risk profile in addition to

leukemia characteristics andresponse to inductionchemotherapy.4 In the current study, the subset ofpatients with low EBMT risk scores showed anexcellent outcome, whereas the GVL effect ofalloHSCT may be blunted by NRM in patientswith a high risk of NRM. Therefore, refined leu-kemia risk scores that predict for relapse should beweighed together with the latest risk scores forNRM.32,38-44 Transplantation risk scores havebeen developed and validated based on patientand transplantation characteristics, including theEBMT risk score32 and the Hematopoietic CellTransplantation-Comorbidity Index,40 which iscontinuously being refined, including age, diseasestatus, or biomarkers.39,41,42 The EBMT AcuteLeukemia Working Party has developed an inte-grated score on the basis of the EBMT-risk scoreand the Hematopoietic Cell Transplantation-Comorbidity Index with increased predictivepower in the setting of RIC alloHSCT.43

Alternatively, a more sophisticated, machine-based learning model was developed by the

Time (months)

CT/autoAlloCox LR P = .20

No.5871

F4040


No.5871

F3832


No.207211

F9390


No.207211

F8355

CT/autoAllo

No. at risk:238180

145151

121128

93100

6571

CT/auto

Allo25

50

75

100

CI o

f Rel

apse

(%)

0 12 24 36 48

A

Time (months)

CT/autoAllo

No. at risk:7158

2339

1934

1628

1422

CT/auto

Allo

25

50

75

100

CI o

f Rel

apse

(%)

0 12 24 36 48

B

Time (months)

CT/auto

Allo

No. at risk:

238

180

145

151

121

128

93

100

65

71

CT/auto

Allo

25

50

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RFS

(%)

0 12 24 36 48

C

Time (months)

CT/auto

Allo

No. at risk:

71

58

23

39

19

34

16

28

14

22

CT/auto

Allo

25

50

75

100

RFS

(%)

0 12 24 36 48

D

Fig 3. Outcome bypostremission treatment(PRT). Kaplan-Meierestimates of the cumulativeincidence (CI) of relapse in(A)minimal residualdisease(MRD)–negative patients;(B) CI of relapse in MRD-positive patients; (C)relapse-free survival (RFS)in MRD-negative patients;and (D) RFS in MRD-positive patients by type ofPRT in patients with acutemyeloid leukemia in firstcomplete remission fromstart of PRT. Of note,numbers of patients at risk(indicated below the x-axis)differ from the patientnumbers (indicated inTable 1 and within thefigure) because of the time-dependent nature of thisanalysis, which allows fortime to transplantation byswitching patients at thetime of allograft in firstcomplete remission to thetransplantation curve.Abbreviations: allo,allogeneic hematopoieticstem-cell transplantation;auto, autologoushematopoietic stem-celltransplantation; CT/auto,chemotherapy or auto; F,numberof failures (ie, deathwhatever the cause); LR,likelihood ratio; No.,number of patients.




EBMT-Acute LeukemiaWorking Party, whichresulted in an alternating decision tree modelwith high predictive power for mortality at100 days, extending to 2 years.44 As advocatedbefore, by weighing both the risk of NRM andthe risk of relapse, a more personalized treat-ment approach can be applied.5 Although thatapproach suits the precision needed for individ-ual patients, itmight also impair the prospective,randomized evaluation of AML treatment ap-proaches, because patient selection may occurat various time points during treatment. Never-theless, the advantages of personalized treatmentare obvious and continuously being refined byupdated and better methods of risk assessment.Also, new technologies to better define MRD,such as quantification of leukemic stem-cellcontent, standardized protocols and antibodypanels, and novel software possibilities, areemerging.45-47

A personalized approach including MRD iden-tifies patients with a high risk of relapse whoqualify for alloHSCT, but who might benefitfrom attempts to induce MRD negativity beforetransplantation. Previously, a number of inves-tigators reported that patients in CR1 with per-sistence of MRD before alloHSCT have worsesurvival compared with recipients of alloHSCT

with an MRD-negative CR1.17,19-24 AlthoughalloHSCT is clearly indicated in MRD-positivepatients, it is important to study the value ofapproaches intended to induce MRD negativitybefore alloHSCT. A prospective inclusion of allMRD-positive patients and subsequently analyz-ing such a strategy in a randomized fashionmightanswer this important question. It has been sug-gested that continued chemotherapy with one ortwoconsolidation cyclesmaynot be the preferredstrategy to obtain an MRD-negative CR beforealloHSCT,48 but several new drugs are currentlybeingdevelopedandevaluated forAML.49Possibleother strategies may include efforts to improveallogeneic immunotherapy by early tapering ofimmunosuppression and/or preemptive donorlymphocyte infusions,which also couldbeguidedby MRD. In addition, the continued applicationof novel post-transplantation strategies, includ-ing epigenetic therapy to enhance theGVLeffect(ie, demethylating agents and histone deacety-lase inhibitors50,51), new agents, such as tyrosinekinase inhibitors for specific molecular muta-tions (ie, FLT3-ITD,52 IDH1/253,54), or targetedimmunotherapy with chimeric antigen recep-tor T cells in MRD-positive patients, may offermore therapeutic options to minimize relapseafter alloHSCT.

Table 3. Multivariable Analysis

Variable

Relapse OS RFS NRM

HR* 95% CI P HR* 95% CI P HR* 95% CI P HR* 95% CI P

PRT (allo v CT/auto) 0.36 0.26 to 0.50 , .001 0.97 0.71 to 1.32 .83 0.53 0.40 to 0.71 , .001 3.01 1.38 to 6.59 .003

MRD (positive v negative) 2.01 1.48 to 2.73 , .001 1.52 1.11 to 2.08 .011 1.70 1.28 to 2.25 , .001 0.74 0.34 to 1.64 .44

Age† 1.19 1.04 to 1.35 .008 1.37 1.20 to 1.58 , .001 1.25 1.11 to 1.41 , .001 1.59 1.18 to 2.13 .001

WBC count at diagnosis(. 100 v < 100; 109/l)

2.36 1.53 to 3.63 , .001 1.66 1.04 to 2.65 .044 1.93 1.27 to 2.94 .004 0.64 0.15 to 2.82 .53

FLT3-ITD category

Low ratio v negative 1.41 0.97 to 2.06 .082 1.54 1.07 to 2.21 .025 1.46 1.05 to 2.04 .030 1.48 0.71 to 3.11 .31

High ratio v negative 2.98 1.60 to 5.56 .002 2.99 1.66 to 5.38 , .001 2.76 1.56 to 4.87 .001 2.49 0.71 to 8.72 .20

ELN2017-risk classification

Intermediate v favorable 2.03 1.40 to 2.96 , .001 1.58 1.06 to 2.34 .024 1.75 1.24 to 2.47 .001 1.13 0.50 to 2.56 .77

Adverse v favorable 3.92 2.65 to 5.81 , .001 3.23 2.18 to 4.79 , .001 3.40 2.38 to 4.84 , .001 2.20 0.99 to 4.89 .051

Late CR v early CR(attained after cycle 2 vcycle 1)

3.00 2.07 to 4.36 , .001 3.37 2.35 to 4.83 , .001 2.80 1.99 to 3.92 , .001 2.07 0.92 to 4.63 .098

Year of PRT 1.12 1.05 to 1.20 , .001 1.02 0.95 to 1.09 .60 1.07 1.00 to 1.13 .033 0.91 0.80 to 1.04 .17

Abbreviations: allo, allogeneic hematopoietic stem-cell transplantation; auto, autologous hematopoietic stem-cell transplantation; CR, complete remission; CT, chemotherapy;ELN2017, European LeukemiaNet 2017; FLT3-ITD, fms-like tyrosine kinase 3 internal tandem duplication; HR, hazard ratio; MRD, minimal residual disease; NRM,nonrelapsemortality (with event death in firstCRand censored at relapse);OS, overall survival (with event deathwhatever the cause); PRT, postremission treatment; relapse,withtime as RFS and with event relapse and censored at death in first CR; RFS, relapse-free survival (with event death in first CR or relapse).*TheHRs are the estimates of the effect of covariables for each outcome parameter, stratified by the number of induction courses and adjusted for type of PRT,MRD status, age,WBC count at diagnosis, FLT3-ITD category, ELN2017-risk, number of cycles to CR, and year of PRT.†Linear with estimates of 10 years difference.




Collectively, our study shows that the GVL effectwas strikingly similar inMRD-positive andMRD-negative patients. The personalized application ofalloHSCT should take MRD response into ac-count, in addition to risk scores forNRM, becauseGVL is not invariably blunted by NRM. Addi-tional prospective studies are needed to evaluatewhether the conversion of MRD positivity into anMRD-negative remissionbeforealloHSCTfurther

optimizes outcome, and how the GVL effect afteralloHSCTcanbeoptimized.Precisionmedicine forpatients with AML is urgently needed; thus, thedecision to perform transplantation or not in anindividual patient might depend on weighing therisk of relapse versus the personalized risk of NRM.

DOI: https://doi.org/10.1200/PO.17.00078Publishedonlineonascopubs.org/journal/poonSeptember15,2017.

AUTHOR CONTRIBUTIONS

Conception and design: Jurjen Versluis, Burak Kalin,Wendelien Zeijlemaker, Bob Lowenberg, Mojca Jongen-Lavrencic, Gerrit Jan Schuurhuis, Gert Ossenkoppele, Jan J.CornelissenAdministrative support: Juergen KuballProvision of study materials or patients: All authorsCollection and assembly of data: All authorsData analysis and interpretation: Jurjen Versluis, BurakKalin, Wendelien Zeijlemaker, Bob Lowenberg, MojcaJongen-Lavrencic, Gerrit Jan Schuurhuis, Gert Ossenkoppele,Jan J. CornelissenManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authors

AUTHORS’ DISCLOSURES OFPOTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided byauthors of this manuscript. All relationships are consideredcompensated. Relationships are self-held unless noted. I =

Immediate Family Member, Inst = My Institution. Relation-shipsmaynot relate to the subjectmatter of thismanuscript. Formore information about ASCO’s conflict of interest policy,please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.

Jurjen VersluisNo relationship to disclose

Burak KalinNo relationship to disclose

Wendelien ZeijlemakerPatents, Royalties, Other Intellectual Property: I have apatent for a laboratory test to identify specific leukemiacells thatcan be used in patients with acute myeloid leukemia. Nofinancial compensation.No relation to current research project(Inst)

Jakob PasswegNo relationship to disclose

Carlos GrauxHonoraria: Novartis, Amgen, Celgene, Roche, Incyte

StudyNo. of Events/Patients HR & 95% CI

(CT/auto : Allo) Reduction

(SD)

MRD status (cut-off 0.1)

Negative 83 / 207 55 / 211

Positive 38 / 58 32 / 71

Total 121 / 265 87 / 282

(46%) (31%)63%(6)

reduction2P < .001 0 0.5 1.0 1.5 2

Allobetter

CT/autobetter

CT/auto Allo

MRD status (cut-off 0.1)

Negative 93 / 207 90 / 211

Positive 40 / 58 40 / 71

Total 133 / 265(50%)

130 / 282(46%) 45%(8)

reduction2P < .001 0 0.5 1.0 1.5 2

Allobetter

CT/autobetter

StudyNo. of Events/PatientsCT/auto

HR & 95% CI(CT/auto : Allo)

Reduction(SD)Allo

A

B

Fig 4. Forest plotsof relapse comparingallogeneic hematopoieticstem-cell transplantation(allo) with chemotherapy(CT) or autologoushematopoietic stem-celltransplantation (auto).Forest plot of pooledestimates of the relativereduction (hazard ratio[HR] and 95% CI) of (A)relapse and (B) relapse-freesurvivalbyminimal residualdisease (MRD) statuscomparing allo withchemotherapy or auto.Abbreviation: SD, standarddeviation.



http://ascopubs.org/doi/full/10.1200/PO.17.00078


http://www.asco.org/rwc

http://po.ascopubs.org/site/ifc


Markus G. ManzConsulting or Advisory Role: Amgen, Novartis, Roche,Pfizer

Marie-Christiane VekemansConsulting or Advisory Role: Amgen (Inst), Celgene (Inst),Bristol-Myers Squibb (Inst), Janssen (Inst), Takeda (Inst)Travel, Accommodations, Expenses:Amgen, Bristol-MyersSquibb, Teva, Janssen

Bart J. BiemondNo relationship to disclose

Marie-Cecile J.C. LegdeurNo relationship to disclose

Marinus Van Marwijk KooyConsulting or Advisory Role: Bristol-Myers SquibbNetherlands

Okke De WeerdtNo relationship to disclose

Pierre W. WijermansNo relationship to disclose

Mels HoogendoornConsulting or Advisory Role: Novartis

Mario J. BargetziNo relationship to disclose

Juergen KuballEmployment: GadetaStock and Other Ownership Interests: GadetaConsulting or Advisory Role: Gadeta, Novartis (Inst)Speakers’ Bureau: GadetaResearch Funding: Gadeta, Miltenyi Biotec, NovartisPatents, Royalties, Other Intellectual Property: Multiplepatents on gamma-delta T cell receptor sequences isolationstrategies and targets in combination with gamma-delta T cellreceptor sequencesTravel, Accommodations, Expenses: Gadeta, Novartis,Miltenyi Biotec

Harry C. SchoutenHonoraria: Gilead Sciences, Novartis, AlexionPharmaceuticals, SanofiTravel, Accommodations, Expenses: AlexionPharmaceuticals

Vincent H.J. van der VeldenConsulting or Advisory Role: Celgene (Inst)Research Funding: BD Biosciences (Inst)Patents, Royalties, Other Intellectual Property: Patent forEuroFlow MRD antibody tubes. No financial relationship(Inst)

Jeroen J.W.M. JanssenHonoraria:Bristol-Myers SquibbNetherlands, Pfizer EuropeConsulting or Advisory Role: Pfizer Europe, NovartisResearch Funding: NovartisTravel, Accommodations, Expenses: Novartis

Thomas PabstNo relationship to disclose

Bob LowenbergConsulting or Advisory Role: Astex Pharmaceuticals,Clear Creek Bio, Agio Pharmaceuticals, Celgene

Mojca Jongen-LavrencicNo relationship to disclose

Gerrit Jan SchuurhuisResearch Funding: Becton Dickinson (Inst)

Gert OssenkoppeleHonoraria: RocheConsulting or Advisory Role: Celgene, SunesisPharmaceuticals, Janssen, Novartis, CTI, Amgen, Pfizer,RocheResearch Funding: Amgen (Inst), Janssen (Inst), Celgene(Inst)Travel, Accommodations, Expenses: Roche

Jan J. CornelissenNo relationship to disclose

ACKNOWLEDGMENTFollowing Dutch-Belgian Hemato-Oncology CooperativeGroup and the Swiss Group for Clinical Cancer Research(HOVON-SAKK) publication rules, coauthorship was offeredto centers contributing the highest number of patients.Nevertheless, the authors highly appreciate the contribution ofmany physicians and data managers throughout HOVON-SAKK, who made this analysis possible.

AffiliationsJurjen Versluis, Burak Kalin, Bob Lowenberg, Mojca Jongen-Lavrencic, and Jan J. Cornelissen, Erasmus University Medical CenterCancer Institute; Vincent H.J. van der Velden, ErasmusUniversityMedical Center, Rotterdam;Wendelien Zeijlemaker, Jeroen J.W.M.Janssen, Gerrit Jan Schuurhuis, and Gert Ossenkoppele, VU University Medical Center; Bart J. Biemond, Academic Medical Center,University of Amsterdam, Amsterdam;Marie-Cecile J.C. Legdeur, Medisch SpectrumTwente, Enschede;Marinus vanMarwijk Kooy,Isala Hospital, Zwolle; Okke de Weerdt, Antonius Hospital, Nieuwegein; Pierre W. Wijermans, Haga Hospital, The Hague; MelsHoogendoorn, Medical Center Leeuwarden, Leeuwarden; Juergen Kuball, University Medical Center Utrecht, Utrecht; Harry C.Schouten, Maastricht University Medical Center, Maastricht, the Netherlands; Jakob Passweg, University Hospital Basel, Basel;Markus G. Manz, University Hospital Zurich, Zurich;Mario J. Bargetzi, Kantonsspital Aarau, Aarau; Thomas Pabst, Inselspital, BernUniversityHospital,Bern,Switzerland;CarlosGraux,Mont-Godinne, Yvoir; andMarie-ChristianeVekemans, CliniquesUniversitairesSaint-Luc, Universite Catholique de Louvain, Brussels, Belgium.




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