Table Of ContentHamiltonetal.JournalofMedicalCaseReports2013,7:18
JOURNAL OF MEDICAL
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CASE REPORTS
CASE REPORT Open Access
Sustained disease-free survival achieved with
withdrawal of immunosuppression after rapid
relapse of myelodysplastic syndrome following
myeloablative allogeneic hematopoietic
transplantation: a case report
Betty K Hamilton1*, Gregory Vereb2 and Edward A Copelan1
Abstract
Introduction: Relapse after allogeneic hematopoietic stemcell transplantation in patients with myelodysplasia is a
challenging problem with limited treatment options. Attempts to induce a graft-versus-leukemia effect have been
used with limited success. Inpatients with myelodysplasia,sustained complete remissions have generally been
limited to patients with long-term remission after transplant and thosewith low numbers ofmarrow blasts.
Case presentation: We report the case of a 41-year-old Caucasian woman with relapsed myelodysplastic
syndrome and a highblast percentage six months after undergoing an allogeneic transplant who achieved a
sustained complete remission after withdrawal of immunosuppression alone.
Conclusion: This case highlights the importance of a reasonable period ofobservation after withdrawing
immunosuppression to induce graft-versus-leukemia,and thepotentialeffectivenessof that approach.
Introduction after allogeneic HSCT who was successfully treated
Allogeneichematopoieticstemcelltransplantation(HSCT) withimmunosuppressionwithdrawal.
is the only curative treatment for patients with myelodys-
plastic syndrome (MDS). Transplant-related complications Case presentation
and disease relapse are the major causes of treatment Our patient was a 41-year-old Caucasian woman who,
failure. Therapeutic options to manage disease relapse are four years prior to her presentation to the Cleveland
limited and virtually all patients ultimately die of their Clinic, was found on routine blood work to be pancytope-
disease or from complications of its treatment. Although nic (white blood cell count (WBC) 3300/mm3 with an ab-
withdrawal of immunosuppression is a common initial solute neutrophil count (ANC) of 1600/mm3, hemoglobin
therapeutic strategy, its limited record of success com- 11.2g/dL, platelet count 104,000/mm3). She noted fatigue
monly results in proceeding rapidly to induction butdeniedothersymptoms.Aninitialbonemarrowbiopsy
chemotherapy and donor lymphocyte infusion (DLI) in showed trilineage dyspoiesis with an increase in atypical
patients with significant numbers of blasts. Chemo- myeloblasts (8%), consistent with MDS, categorized as
therapy,second transplants and DLI areoften usedbut refractory anemia with excess blasts (RAEB-1). A cytogen-
carry a high degree of morbidity and mortality. Here eticanalysisrevealedanormalfemalekaryotype.Herinitial
we present the case of a patient with relapsed MDS score on the International Prognostic Scoring System
(IPSS) was 0.5, or intermediate-1 risk group. She did not
*Correspondence:[email protected] requiretransfusionsandherserumferritinwas11.3ng/mL.
1BoneMarrowTransplantProgram,DepartmentofHematologicOncology A subsequent bone marrow biopsy approximately six
andBloodDisorders,ClevelandClinicTaussigCancerInstitute,9500Euclid
months later demonstrated a rising blast percentage to
Avenue,Cleveland,OH44195,USA
Fulllistofauthorinformationisavailableattheendofthearticle 15%, consistent with MDS RAEB-2. Our patient’s blood
©2013Hamiltonetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
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counts declined very gradually and remained largely origin.Peripheralbloodcountsonday153demonstrateda
stable over the next three years. The blast count on WBC of 1700/mm3, ANC 650/mm3, hemoglobin 9.3g/dL,
repeat bone marrows over this time period remained in and a platelet count of 124,000/mm3 with 10% circulating
the 10% to 15% range. Cytogenetic analysis continued to blasts. Our patient’s immunosuppression (cyclosporine and
demonstrate a normal female karyotype. She remained mycophenolatemofetil)wasstoppedday153andinduction
asymptomatic and declined therapy, despite the elevated chemotherapyandDLIwereplanned.
blast count. She began to develop worsening cytopenias Our patient was admitted to an outside hospital for
despite a stable blast percentage on repeat bone marrow fever and chest pain the following week. Blood counts at
biopsies and she subsequently developed worsening that time revealed a WBC of 8000/mm3 and an ANC of
anemia requiring red blood cell transfusions. As she 1500/mm3 with no circulating blasts. She was found to
became more symptomatic, she agreed to proceed with have pneumonia with an associated parapneumonic
allogeneic HSCT from her brother, who had previously pericardial effusion. She underwent pericardiocentesis
been identified to be human leukocyte antigen (HLA)- and was transferred to our institution, where she com-
identical. A pretransplant bone marrow biopsy revealed pleted a course of intravenous antibiotics. During her
high-grade MDS with 15% blasts. One month later, she hospitalization,herWBCandANCremainedinthenormal
underwent HSCT following high-dose intravenous range with no evidence of circulating blasts. On follow-up,
busulfan (12.8mg/kg) and cyclophosphamide (120mg/kg). approximately a month after stopping immunosuppresion,
Graft-versus-host disease (GVHD) prophylaxis consisted ourpatientdevelopedanerythematous,pruriticrashonher
ofcyclosporineandmycophenolatemofetil. upper and lower extremities, accounting for approximately
Four weeks after the transplant she developed an 50%of herbodysurfacearea.Countsatthistimedropped,
erythematous, pruritic skin rash on her chest, accounting withaWBCof98/mm3,hemoglobin8.3g/dL,andaplatelet
for approximately 25% of her body surface area. Results count of 5000/mm3. A skin biopsy confirmed grade 2
from a skin biopsy confirmed grade 2 acute GVHD. She GVHD. A bone marrow biopsy done the same day, five
also developed nausea and vomiting suggestive of upper weeks after stopping immunosuppression, demonstrated a
gastrointestinal tract GVHD, although this was not hypocellular bone marrow with no evidence of MDS.
confirmed on histology. She was treated with 1mg/kg of Engraftment analysis on day 181 demonstrated only 1% of
prednisone and continued mycophenolate and cyclo- peripheral blood leukocyteDNAofrecipient origin and no
sporine. Her GVHD symptoms resolved and she was recipientDNAintheT-cellenrichedfraction.
taperedoffprednisoneby18weekspost-transplantation. Therashprogressedoverthenexttwoweeks,becoming
Within this same time frame, it was first noted 125 days more erythematous and pruritic, and demonstrating
post-transplant that her blood counts had decreased features of both acute and chronic GVHD. Her liver
(WBC, 1450/mm3; ANC, 870/mm3; hemoglobin, 9.7g/dL; function tests were also mildly elevated. Prednisone
plateletcount,83,000/mm3)althoughourpatientfeltwell. 1mg/kg was initiated and lead to a gradual improvement
Anengraftmentanalysisfromherperipheralbloodonthe of her rash and liver function tests, and she was tapered
same day, which had previously demonstrated complete off immunosuppression over a six-month period. Her
donor leukocyte and T-cell chimerism, demonstrated 3% bloodcountsnormalizedbyday209andshecontinuedto
of the peripheral blood leukocyte deoxyribonucleic acid demonstratecompletedonorchimerism.Interestingly,she
(DNA) of recipient origin and 41% of theT-cell-enriched developedintermittentneutropeniaduringhertaper,how-
fraction containing DNA of recipient origin. Her blood ever this would recover spontaneously and she continued
counts continued to decline. Sixteen days later, approxi- to demonstrate complete donor chimerism on engraft-
mately five months after transplantation, her WBC was ment studies. Her counts have subsequently completely
940/mm3,ANC430/mm3,hemoglobin8.0g/dLandplatelet normalized.Ourpatientiscurrentlymorethanthreeyears
count89,000/mm3. from her allogeneic transplant and more than two and a
By day 143, a peripheral smear showed a WBC of half years from stopping immunosuppression. She con-
1240/mm3, ANC 520/mm3, hemoglobin 10.1g/dL, and a tinues to do exceedingly well, training for and running in
plateletcountof102,000/mm3with1%circulatingblasts. half-marathons regularly. Her blood counts are normal
A bone marrow biopsy at this time, now six months after andherleukocytesandT-cellsare100%donor.
transplantation, demonstrated relapsed MDS with 12%
blasts. Cytogenetic analysis showed mixed chimerism but Discussion
anormalkaryotype,46,XX/46,XY. ThecurativeeffectofHSCTresultsnotonlyfromtheradi-
A repeat engraftment analysis on day 153 confirmed ation and/or chemotherapy in the conditioning regimen,
increasingrecipientchimerism,with 42%oftheperipheral but also from a graft-versus-leukemia (GVL) effect exerted
blood leukocyteDNAofrecipient origin and 65%ofthe by the donor-derived immune system. The demonstration
T-cell-enriched fraction containing DNA of recipient that donor T-cells inhibit the growth of leukemia colonies
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invitroandeliminateleukemia stem cells,asassessedbya chemotherapy or DLI. Results after myeloablative trans-
model of engraftment and propagation of leukemia in plantareevenlessencouraging[9,10].
immunologically susceptible mice, indicate that this im- A large series evaluating immunosuppression withdrawal
munologiceffectcanbecurative[1,2].Thelowerincidence demonstrated durable remissions in 84% of patients with
of relapse in patients who develop GVHD supports the CML, underscoring the strong GVL effect in CML,
contribution of the donor-derived immune system to the whereas only 10% of patients with AML and no advanced
eradication of malignant cells [3]. The prevention or CMLor acute lymphoblasticleukemiaachieved remissions
moderationofGVHDwithoutlossofaGVLeffectremains atthreeyears[11].Successwaslimitedtopatientswhohad
asignificantandunsolvedchallenge. sustainedcompleteremissionaftertransplantandwhohad
Disease relapse is the most frequent cause of treatment low numbers of blasts. Patients with MDS who relapse
failureafterallogeneicHSCTofMDS.Relapseriskdepends shortly after myeloablative transplants with high numbers
on remission status at the time of transplant, cytogenetic of blasts have not achieved sustained remission after with-
and molecular abnormalities of the MDS cells, and other drawal ofimmunosuppressionaloneandgenerallyproceed
factors. Patients with MDS who relapse after transplant- rapidlytomoreaggressivetherapyifappropriate.
ation have dismal prognoses and there is no standard The efficacy of DLI in MDS has been evaluated with a
effective treatment strategy. Options include intensive response rate of 14% to 40% [12,13]. DLI has been
chemotherapyandDLI, or second transplants,all ofwhich effective in inducing long-term remission in a small
are associated with high mortality rates and have achieved subset of patients with MDS; however, responses are
only very limited degrees of success [4]. Novel approaches associated with severe GVHD, which can result in
to enhance the GVL effect using donor-derived natural significant transplant-related morbidity and mortality.
killercellsarebeingstudied[5]. The incidence rates of acute and chronic GVHD varied
WithdrawalofimmunosuppressionandDLIhasbeen from 34% to 60% and 14% to 33%, respectively. In one
moderately successful in the treatment of relapsed small series, patients who were higher risk on the IPSS
chronic myelogenous leukemia (CML), which is highly appeared to have a better response to DLI than those
sensitive to the GVL effect. High relapse rates after with lower-intermediate risk IPSS [13]. While low tumor
T-cell depletionoftheallograftinCMLtransplantation burdengenerallyisapredictorofresponsetoDLI,MDSis
has been well documented and support the sensitivity a clinically and molecularly heterogeneous group, and one
of CML to GVL [3]. Reports of individual patients who may speculatethat thesusceptibility to immunologictreat-
relapse after transplantation but achieve remission ment or GVL effect may be impacted by the cytogenetic
when immunosuppression was stopped and GVHD andmolecularcharacteristicsoftheMDSclone.
flared, and the effectiveness of DLI in achieving long- Thedifficultyofdeterminingwhomaybesusceptibleto
term remission in patients who have relapsed provide immunologic treatment or the GVL effect was recently
furtherevidenceofthis. illustrated by a report of patients who relapsed after
By contrast, patients with MDS and acute myelogenous haploidentical transplantation [14]. In five of 17 patients’
leukemia (AML) who relapse after HSCTare a heteroge- mutant leukemic cells, the HLA haplotype that differed
neousgroupandthereisnosinglestandardapproach.Out- fromthedonorwaslostatrelapseduetoacquiredunipar-
comeswithaggressivechemotherapy,DLIorsecondHSCT ental disomy of chromosome 6p. Thus, T-cells from the
aregenerallypoor [6-8]. The few who benefit are generally donorthathadrecognizedandkilledtheoriginalleukemic
younger patients with good performance status and long cellsnolongerrecognizedthemutantleukemiccells.
disease-free interval after transplant [4]. Immunosuppres- Othertherapies,suchashypomethylatingagents,withor
sionwithdrawalalonehasrarelybeenreportedtoachievea without DLI or second transplants, also warrant further
meaningful response after myeloablative transplantation in investigation in this setting. A recent report demonstrated
MDSorAML[9,10]. the safety and efficacy of azacitidine as a treatment for
Researchers at the MD Anderson Cancer Center minimal residual disease [15]. Twenty patients with de-
reported durable remissions in a small subset of patients creasing donor chimerism were treated with four cycles of
withMDSorAMLwhohadrelapsedafterreducedinten- azacitidineand80%ofthesepatientsrespondedwitheither
sity, not myeloablative, regimens and undergone second increasing donor chimerism or stabilization in the absence
HSCT, but dismal outcomes in patients who had their of relapse. Although relapse eventually occurred in 65% of
immunosuppressionwithdrawnorwhoreceivedDLI[11]. thesepatients,timetorelapsewassignificantlydelayed.
Only6.6%ofpatientsachievedacompleteremissionafter There remains significant variability in regards to
immunosuppression withdrawal; and unlike our patient, long-term disease control in patients with MDS who
all had less than 10% blasts in their bone marrow and no relapse after transplant. Several factors are involved,
circulating blasts. Most of those who did not respond to includingthediseasestatusattimeoftransplant,remission
immunosuppression withdrawal were treated with further duration, disease tempo at time of relapse, molecular and
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Abbreviations 12. DepilS,DeconinckE,MilpieN,SuttonL,WitzF,JouetJP,DamajG,Yakoub-
AML:Acutemyelogenousleukemia;ANC:Absoluteneutrophilcount; AghaI:Donorlymphocyteinfusiontotreatrelapseafterallogeneicbone
CML:Chronicmyelogenousleukemia;DLI:Donorlymphocyteinfusion; marrowtransplantationformyelodysplasticsyndrome.BoneMarrow
GVHD:Graft-versus-hostdisease;GVL:Graft-versus-leukemia;HLA:Human Transplant2004,33:531–534.
leukocyteantigen;HSCT:Hematopoieticstemcelltransplantation; 13. CampregherPV,GooleyT,ScottBL,MoravecC,SandmaierB,MartinPJ,
IPSS:InternationalPrognosticScoringSystem;MDS:Myelodysplastic DeegHJ,WarrenEH,FlowersME:Resultsofdonorlymphocyteinfusions
syndrome;WBC:Whitebloodcellcount. forrelapsedmyelodysplasticsyndromeafterhematopoieticcell
transplantation.BoneMarrowTransplant2007,40:965–971.
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Authordetails
doi:10.1186/1752-1947-7-18
1BoneMarrowTransplantProgram,DepartmentofHematologicOncology
Citethisarticleas:Hamiltonetal.:Sustaineddisease-freesurvival
andBloodDisorders,ClevelandClinicTaussigCancerInstitute,9500Euclid
achievedwithwithdrawalofimmunosuppressionafterrapidrelapseof
Avenue,Cleveland,OH44195,USA.2WakeForestSchoolofMedicine, myelodysplasticsyndromefollowingmyeloablativeallogeneic
Winston-Salem,NC,USA. hematopoietictransplantation:acasereport.JournalofMedicalCase
Reports20137:18.
Received:9August2012Accepted:1December2012
Published:14January2013
