Available online at www.sciencedirect.com

Leukemia Research 32 (2008) 14681471

Case report

Secondary myelodysplastic syndromphlecatine Con a, Fson Can

b Dep of Texbruary 2

2008

Abstract

The addition of imatinib to high-intensity chemotherapy has improved the outcome of patients with Philadelphia chromosome (Ph)-positiveacute lymphoblastic leukemia (ALL). However, the possible long-term side effects of this combination are not yet known. Development ofnew clonal abnormalities in complete cytogenetic remission after treatment with imatinib has been reported in patients with chronic myeloidleukemia but not in patients with Ph-positive ALL. Here, we present a patient with Ph-positive ALL who received hyperCVAD plus imatiniband achievecentral nerv 2008 Else

Keywords: Ph

1. Introdu

Most adlymphoblasis. Aboutachieve a cing on thesurvival rain patientsAdding imABL oncoimproved tside effectunknown.

CorresponE-mail ad

0145-2126/$doi:10.1016/jd hematologic, cytogenetic, and major molecular responses. The patient then developed myelodysplastic syndrome and solitaryous system relapse of ALL.vier Ltd. All rights reserved.

iladelphia-positive acute lymphoblastic leukemia; Imatinib mesylate; Myelodysplastic syndrome

ction

ult patients with Philadelphia (Ph)-positive acutestic leukemia (ALL) have a dismal progno-

8085% of patients with Ph-positive ALLomplete hematologic response (CHR), depend-treatment regimen; however, the disease-free

te at 2 years is estimated to be only 1015%who are treated with only chemotherapy [1].

atinib mesylate, a specific inhibitor of the BCR-protein, to standard chemotherapy regimens hashe event-free survival [24], but the long-terms of imatinib mesylate therapy, if any, are still

ding author. Tel.: +1 713 745 0394; fax: +1 713 745 4612.dress: fravandi@mdanderson.org (F. Ravandi).

Several studies have reported the development of newclonal abnormalities in Ph-negative metaphases after treat-ment with imatinib in patients with chronic myeloid leukemia(CML) [511]. A number of these patients have dysplasticfeatures in their bone marrow, and a few patients devel-oped acute myeloid leukemia (AML) [5,7,1214]. However,the relationship between the development of cytogeneticabnormalities, myelodysplastic syndrome (MDS), or acuteleukemia and treatment with imatinib is not clear. Manypatients treated with imatinib develop cytopenias and dys-plastic changes in their bone marrow. However, in most cases,these abnormalities are transient [15,16]. Whether imatinibinduces MDS remains to be established.

Here, we report a patient with Ph-positive ALL whoreceived hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone (hyperCVAD) plus imatinib.After 11 months of therapy, the patient developed MDS. Herclinical course was further complicated by the development

see front matter 2008 Elsevier Ltd. All rights reserved..leukres.2008.02.001Philadelphia-positive acute lymafter achieving a major mowith hyperCVAD plus im

Arturo Vega-Ruiz a, Susan OBrien a, JorgDeborah Thomas a, Hagop Kantarjia

a Department of Leukemia, The University of Texas M. D. Anderartment of Stem Cell Transplantation and Cellular Therapy, The University

Received 8 November 2007; received in revised form 5 FeAvailable online 19 Marche in a patient withoblastic leukemiaular responseib mesylate

rtes a, Partow Kebriaei b,arhad Ravandi a,cer Center, Houston, TX 77030, USAas M. D. Anderson Cancer Center, Houston, TX, USA008; accepted 6 February 2008

A. Vega-Ruiz et al. / Leukemia Research 32 (2008) 14681471 1469

of a CNS relapse shortly after, though the patient remainedin complete hematologic, cytogenetic, and major molecularremission.

2. Case re

A 62-yelocal practiand fatiguea white blophysical exBone marropre-B-cell ACD13 dim,TdT). A chchromosomb3a2 BCRtranscript ra(LP) reveal

In MayhyperCVADwas givenfirst treatmthe transcrnotype anaresidual disbrospinal flof intratheCNS infiltintrathecalmore week

Followiremainedcomplete csitu hybridMRD, andDue to theple co-morSeptembertenance the800 mg/day

In Novetherapy, cypseudodipland del(20metaphasestic cells, alblasts. Flowand the BCthe patientregimen.

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ar-old woman presented in March 2006 to hertioner with recurrent sinus infections, bone pain,. Evaluation of the patients blood count revealedod cell count of 22 109/L, with 82% blasts. Aamination did not show any remarkable findings.w examination was consistent with a diagnosis ofLL (immunophenotype positive for CD9, CD10,CD19, CD22, CD25, CD34, CD38, CD79a, and

romosome analysis revealed the presence of the Phe and trisomy 8. Molecular studies detected the

-ABL fusion transcript, and the BCR-ABL/ABLtio was 53.5 (Table 1). The initial lumbar punctureed CNS infiltration.2006, the patient began induction therapy with

plus oral imatinib mesylate 600 mg/day, whichthroughout the course of treatment. After theent cycle, the patient achieved a CHR, andipt ratio decreased to 0.14. The immunophe-lysis indicated that in spite of CHR, minimalease (MRD) was still present. The patients cere-uid (CSF) became negative after the third roundcal chemotherapy. A subsequent LP found noration. Subsequently, LPs were performed andchemotherapy was administered weekly for 6

s.ng the fifth course of treatment, the patientin CHR, and a bone marrow biopsy showedytogenetic remission, negative fluorescence inization (FISH), negative flow cytometry fora BCR-ABL/ABL transcript ratio of 0.003.patients poor performance status and multi-

bidities, intensive chemotherapy was stopped in2007. The patient then began receiving main-rapy with prednisone, vincristine, and imatinib.

mber 2006, 3 months after starting maintenancetogenetic analysis of bone marrow revealed aoid clone, inv(6)(p21.1p22) in two metaphases)(q11.2p13.3) in one metaphase. These abnormal

suggested an emergent population of neoplas-though there was no dysplasia and no increase in

cytometry and FISH were negative for MRD,R-ABL/ABL transcript ratio was 0.08. Clinically,remained stable, and continued the maintenance

h 2007, the dose of imatinib was reduced todue to the development of fluid retention. The

developed cytopenias without the need for growthpy or transfusions. In April 2007, a repeat bone

1470 A. Vega-Ruiz et al. / Leukemia Research 32 (2008) 14681471

marrow exam showed no blasts but 34% monocytes andoccasional promonocytes, with dyserythropoiesis which sug-gested therapy-related MDS. She also developed peripheralblood monattributed tsis, a pseuand FISHrearrangemthe previouconcludedmalities reclassified aFrenchAmremained nratio was le

In Augtransplanta markedremainedprior to stleukemic cthese cellsABL by pochemotheraCSF. She thcell transplof active lextramedulwithout cyt

3. Discuss

In thisachieved hchemotherament, she aWhile receprednisonemorphologtoxic agenof MDS wing agentsin chromotopoisomermitoxantrotions involMethotrexainteract winonhomolohas beentinib whomolecularin Ph-negareported infrequent c

somy 5 or 7, and 20q and changes in chromosome Y[57].

Our patient developed clonal abnormalities 7 months afteritiatio

e therae eve

) andd withgenemia)which

chromthat ah clonry AMteratudarynib thur pah wassis anosis,ntral

hylaximia,of paAnec

ALLeneticbeen

e inaband aerebroCNS rimpertomse inhidecreamias.

ict of

e autiaei, Dof intved re

owled

ontribn OB

Corteebriaanagocytosis, up to 3.7 109/L, that could not beo any other ongoing process. On karyotype analy-dodiploid clone t(4;11)(q21;q23) was identified,was positive for a clone with an MLL geneent. The inv(6) and del(20) clones present ins cytogenetic test were not seen. It was then

that the monocytosis and clonal cytogenetic abnor-presented therapy-related MDS. This case wass chronic myelomonocytic leukemia type 1 byericanBritish criteria. Flow cytometry results

egative for MRD. The BCR-ABL/ABL transcriptss than 0.01.ust 2007, the patient underwent a stem cellevaluation. The patient was asymptomatic, withimprovement in her performance status, andin major molecular remission. The work-upem cell transplant revealed CNS infiltration byells, and immunophenotype analysis revealedto be lymphoblasts; CSF was positive for BCR-lymerase chain reaction. After further intrathecalpy, the BCR-ABL fusion disappeared from theen underwent a matched sibling allogeneic stem

ant. At the latest follow-up, she had no evidenceeukemia in her bone marrow, and no CNS orlary disease. She had full donor hematopoiesisogenetic abnormalities.

ion

case report, our patient with Ph-positive ALLematological remission after the first course ofpy with imatinib. After five courses of treat-

lso achieved cytogenetic and molecular remission.iving maintenance with imatinib, vincristine and, she developed new clonal abnormalities andical findings associated with MDS. Several cyto-ts have been associated with the developmentith specific chromosomal abnormalities. Alkylat-are mostly associated with losses or deletions

some 7 and/or 5, while drugs targeting DNA-ase II (e.g., etoposide, doxorubicin, daunorubicin,ne) have been associated with balanced transloca-ving chromosome bands 11q23 and 21q22 [17].te and 6-mercaptopurine have been reported toth DNA repair, leading to point mutations andgous recombination [18]. Development of MDS

reported in patients with CML receiving ima-achieve complete hematologic, cytogenetic, andresponses [1214]. Chromosomal abnormalitiestive metaphases after imatinib therapy have been

217% of patients with CML [5]. The mostytogenetic abnormalities are trisomy 8, mono-

the innanc

but w(4;11ciateMLLleukeminenew

siblethe Pondathe lisecon

imatiO

whicanalydiagnof cepropleuke10%[22].Ph +cytoghaveto thrierthe ctaryit issympkinastherleuke

Con

ThKebrflictrecei

Ackn

CSusaJorgetow Kand mn of chemotherapy and while receiving mainte-py. The abnormalities initially were nonspecific,ntually detected a clone with the translocationMLL gene rearrangement, findings clearly asso-

MDS and acute leukemia. Around 510% ofassociated leukemias (i.e., myeloid or lymphoidare therapy related [1921]. We could not deter-

drug was responsible for the development of theosomal abnormality in our patient. It is also pos-silent clone present at the onset, emerged aftere was partially eliminated. Other reports of sec-L or MDS occurring after ALL therapy exist in

re [17]; however, to our knowledge, no cases ofMDS have been reported after hyperCVAD pluserapy.tient also developed a solitary CNS relapse,

confirmed to be ALL by immunophenotyped polymerase chain reaction for BCR-ABL. At510% of patients with ALL have evidencenervous system (CNS) disease. Without CNSs, up to 30% of patients will develop CNSand despite adequate CNS prophylaxis, up totients will eventually develop a CNS relapsedotal reports of CNS relapse in patients withdespite achievement of complete hematologic,

and molecular responses in the bone marrowpublished recently [2226]. This may be dueility of imatinib to cross the bloodbrain bar-chieve adequate therapeutic concentrations inspinal fluid [2226]. Therefore, although soli-elapse is uncommon after adequate prophylaxis,ative to suspect it in patients with appropriateeven in remission. Development of new tyrosinebitors that cross the bloodbrain barrier may fur-se the incidence of CNS relapse in Ph-positive

interest

hors Arturo Vega-Ruiz, Susan OBrien, Partoweborah Thomas and Farhad Ravandi have no con-

erest. Jorge Cortes and Hagop Kantarjian havesearch funding from Novartis Pharmaceuticals.

gements

utions: Arturo Vega-Ruiz wrote the manuscript.rien managed the patient and the clinical trial.s managed the patient and the clinical trial. Par-ei managed the patient. Deborah Thomas wroteed the clinical trial. Hagop Kantarjian managed

A. Vega-Ruiz et al. / Leukemia Research 32 (2008) 14681471 1471

the clinical trial. Farhad Ravandi reviewed and edited themanuscript, managed the patient.

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Secondary myelodysplastic syndrome in a patient with Philadelphia-positive acute lymphoblastic leukemia after achieving a major molecular response with hyperCVAD plus imatinib mesylateIntroductionCase reportDiscussionConflict of interestAcknowledgementsReferences