chronic myeloid leukemia as a secondary malignancy after lymphoma in a child. a case report and...

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Case Report · Kasuistik Onkologie 2012;35:690–693 Published online: October 22, 2012 DOI: 10.1159/000343952 Dr.KmiraZahra DepartmentofClinicalHematology FarhatHachedUniversityHospitalSousse-Tunisia AvenueIbnEljazzarSousse4000,Tunisia [email protected] ©2012S.KargerGmbH,Freiburg 0378-584X/12/3511-0690$38.00/0 Accessibleonlineat: www.karger.com/onk Fax+497614520714 [email protected] www.karger.com Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature Kmira Zahra a Wafa Ben Fredj a Yosra Ben Youssef a Houneida Zaghouani b Imène Chebchoub c Monia Zaier a Sriha Badreddine d Nejia Braham e Hlima Sennana f Abderrahim Khelif a a Department of Clinical Hematology, b Department of Radiology, c Department of Oncology, d Department of Anatomopathology, e Department of Cytology, f Department of Cytogenetics, Farhat Hached University Hospital Sousse-Tunisia, Tunisia Schlüsselwörter Chronische myeloische Leukämie · Diffus großzelliges B-Zell-Lymphom · Therapie Zusammenfassung Hintergrund: Die Philadelphia-Chromosom-positive chronisch myeloische Leukämie (CML) tritt bei Kindern nur sehr selten auf. CML als sekundäre Tumorerkran- kung bei Patienten mit primärem diffus großzelligen B-Zell-Lymphom (DLBCL) ist ebenfalls ein seltenes Er- eignis. Fallbericht: Wir berichten von einer 5-jährigen Patientin mit einem als DLBCL diagnostizierten Tumor in der rechten Orbita. 9 Monate nach Behandlung des DLBCL wurde die Patientin mit einer Leukozytenzahl von 250 000/mm 3 vorstellig. Die Untersuchung des periphe- ren Blutes und des Knochenmarks ergaben eine myelo- proliferative Erkrankung. Die zytogenetische and mole- kulare Untersuchung zeigten das Vorliegen von t(9;22). Das Auftreten einer CML nach DLBCL bei jüngeren Pati- enten ist bisher nicht beschrieben worden. Unseres Wis- sens ist dies der erste Bericht einer sekundären CML nach primärem DLBCL bei einem Kind. Therapiebezo- gene CML und nicht therapiebezogene sekundäre CML werden als potentielle Erklärungen für diese äußerst un- gewöhnliche klinische Präsentation diskutiert. Schluss- folgerung: Hämatologische Erkrankungen wie die CML können im Anschluss an ein Lymphom auftreten. Mit dem steigenden Einsatz zytogenetischer Knochenmarks- studien im Staging lymphoider Tumorerkrankungen soll- ten zukünftige Studien die Frage beantworten können, ob der CML-Klon bei manchen dieser Patienten bereits vor der Lymphom-Therapie vorlag. Keywords Chronic myeloid leukemia · Diffuse large B-cell lymphoma · Therapy Summary Background: Philadelphia chromosome-positive chronic myeloid leukemia (CML) in children is very rare. CML occurring as a secondary malignancy in individuals treated for diffuse large B-cell lymphoma (DLBCL) is also rare. Case Report: We present the case of a 5-year-old female patient who developed a right orbital mass that was diagnosed as DLBCL. 9 months after receiving treat- ment for DLBCL, she presented with a white cell count of 250,000/mm 3 . Peripheral blood and bone marrow (BM) evaluation revealed a myeloproliferative disorder. Cyto- genetic and molecular studies demonstrated the pres- ence of t(9;22). CML following DLBCL has not been previ- ously described in the younger population. To our knowledge, this is the first report of a child who devel- oped a CML as a second malignancy after DLBCL. Ther- apy-related CML and non-therapy-related secondary CML are discussed as potential explanations of this highly unusual clinical presentation. Conclusion: Hema- tological disorders such as CML may occur after lympho- mas. With the increased use of BM cytogenetic studies during staging for lymphoid malignancies, future studies may be able to clarify the question of whether the CML clone in some of these patients existed before treatment for lymphoma. Downloaded by: Lulea Tekniska Universitet 130.240.43.43 - 8/25/2013 12:15:52 PM

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Page 1: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature

Case Report · Kasuistik

Onkologie 2012;35:690–693� Published online: October 22, 2012

DOI: 10.1159/000343952

Dr.�Kmira�Zahra�Department�of�Clinical�HematologyFarhat�Hached�University�Hospital�Sousse-TunisiaAvenue�Ibn�Eljazzar�Sousse�4000,�[email protected]

©�2012�S.�Karger�GmbH,�Freiburg0378-584X/12/3511-0690$38.00/0

Accessible�online�at:�www.karger.com/onk

Fax�+49�761�4�52�07�[email protected]

Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the LiteratureKmira Zahraa Wafa Ben Fredja Yosra Ben Youssefa Houneida Zaghouanib Imène Chebchoubc Monia Zaiera Sriha Badreddined Nejia Brahame Hlima Sennanaf Abderrahim Khelifa

aDepartment of Clinical Hematology, bDepartment of Radiology, cDepartment of Oncology, dDepartment of Anatomopathology,eDepartment of Cytology, fDepartment of Cytogenetics, Farhat Hached University Hospital Sousse-Tunisia, Tunisia

SchlüsselwörterChronische myeloische Leukämie · Diffus großzelliges B-Zell-Lymphom · Therapie

ZusammenfassungHintergrund: Die Philadelphia-Chromosom-positive chronisch myeloische Leukämie (CML) tritt bei Kindern nur sehr selten auf. CML als sekundäre Tumorerkran-kung bei Patienten mit primärem diffus großzelligen B-Zell-Lymphom (DLBCL) ist ebenfalls ein seltenes Er-eignis. Fallbericht: Wir berichten von einer 5-jährigen Patientin mit einem als DLBCL diagnostizierten Tumor in der rechten Orbita. 9 Monate nach Behandlung des DLBCL wurde die Patientin mit einer Leukozytenzahl von 250 000/mm3 vorstellig. Die Untersuchung des periphe-ren Blutes und des Knochenmarks ergaben eine myelo-proliferative Erkrankung. Die zytogenetische and mole-kulare Untersuchung zeigten das Vorliegen von t(9;22). Das Auftreten einer CML nach DLBCL bei jüngeren Pati-enten ist bisher nicht beschrieben worden. Unseres Wis-sens ist dies der erste Bericht einer sekundären CML nach primärem DLBCL bei einem Kind. Therapiebezo-gene CML und nicht therapiebezogene sekundäre CML werden als potentielle Erklärungen für diese äußerst un-gewöhnliche klinische Präsentation diskutiert. Schluss-folgerung: Hämatologische Erkrankungen wie die CML können im Anschluss an ein Lymphom auftreten. Mit dem steigenden Einsatz zytogenetischer Knochenmarks-studien im Staging lymphoider Tumorerkrankungen soll-ten zukünftige Studien die Frage beantworten können, ob der CML-Klon bei manchen dieser Patienten bereits vor der Lymphom-Therapie vorlag.

KeywordsChronic myeloid leukemia · Diffuse large B-cell lymphoma · Therapy

SummaryBackground: Philadelphia chromosome-positive chronic myeloid leukemia (CML) in children is very rare. CML occurring as a secondary malignancy in individuals treated for diffuse large B-cell lymphoma (DLBCL) is also rare. Case Report: We present the case of a 5-year-old female patient who developed a right orbital mass that was diagnosed as DLBCL. 9 months after receiving treat-ment for DLBCL, she presented with a white cell count of 250,000/mm3. Peripheral blood and bone marrow (BM) evaluation revealed a myeloproliferative disorder. Cyto-genetic and molecular studies demonstrated the pres-ence of t(9;22). CML following DLBCL has not been previ-ously described in the younger population. To our knowledge, this is the first report of a child who devel-oped a CML as a second malignancy after DLBCL. Ther-apy-related CML and non-therapy-related secondary CML are discussed as potential explanations of this highly unusual clinical presentation. Conclusion: Hema-tological disorders such as CML may occur after lympho-mas. With the increased use of BM cytogenetic studies during staging for lymphoid malignancies, future studies may be able to clarify the question of whether the CML clone in some of these patients existed before treatment for lymphoma.

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Page 2: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature

Onkologie�2012;35:690–693Secondary�Chronic�Myeloid�Leukemia 691

was�only�started�4�months�after�the�diagnosis�of�CML�(December�2010),�due�to�a�delay�in�funding�by�the�National�Social�Security�Fund.�The�pa-tient� received� imatinib�at� a�dose�of�340�mg/m2.�However,� 15�days�after�starting�imatinib,�she�developed�severe�thrombocytopenia�(<�10,000/mm3)�with� bleeding� requiring� drug� discontinuation.� The� thrombocytopenia�failed�to�improve,�and�a�BM�aspirate�performed�in�January�2011�–�15�days�after� imatinib� discontinuation� –� eliminated� an� acutization� of� the� CML�(8%�blasts�and�10%�promyelocytes).� In�February�2011�–�1�month�after�imatinib�discontinuation�–�the�patient’s�blood�cell�count�was�as�follows:�hemoglobin� 10� g/dl,� white� blood� cell� count� 126,000/mm3,� platelet� count�16,000/mm3,�25%�neutrophils,�6%�lymphocytes,�3%�eosinophils,�2%�ba-sophils,�3%�erythroblasts,�35%�myelocytes�+�metamyelocytes,�18%�pro-myelocytes,� and� 8%� blasts� in� a� peripheral� smear.� The� BM� aspirate�showed� transformation� of� the� CML� into� acute� myeloblastic� leukemia�(AML)�with�37%�medullary�blasts�(fig.�3).�Flow�cytometric�examination�of� the�BM�cells�revealed�a�notable�blastic�population�estimated�at�35%�positive�for�CD45,�CD34,�CD58,�CD13,�CD65,�CD117,�CD33,�CD15,�and�cMPO,�consistent�with�the�diagnosis�of�AML.�Cytogenetic�BM�study�re-vealed�a�45,XX,t(9;22)(q34;q11)-4/46,X,del(X)(q22),t(9;22)(q34;q11),i(9)(q10)-4/46,XX,der(9)t(4;9)(q21,p21)t(9;22)(q34;q11)-12� karyotype.� The�patient� was� given� a� course� of� systemic� chemotherapy� according� to� the�French�ELAM02�protocol� [4]�consisting�of�mitoxantrone�hydrochloride�

Introduction

Diffuse�large�B-cell� lymphoma�(DLBCL)�makes�up�10–20%�of� pediatric� non-Hodgkin’s� lymphoma� (NHL),� and� these��patients� have� a� significantly� better� prognosis� than� adults��with�DLBCL�[1].�Chronic�myeloid�leukemia�(CML)�in�child-hood�is�rare,�accounting�for�less�than�10%�of�all�cases�of�CML�and� less� than� 3%� of� all� pediatric� leukemias.� The� incidence��increases� with� age,� being� exceptionally� rare� in� infancy� with�0.7/million/year� at� ages� 1–14� years� and� rising� to� 1.2/million/year�in�adolescents�[2].�It�is�also�exceedingly�rare�as�a�second-ary� �malignancy� in� children.� In� this� report,� we� present� the��unusual�occurrence�of�CML�9�months�after�the�treatment�of�DLBCL�in�a�child.�

Case Report

A� 5-year-old� female� patient� presented� in� June� 2009� with� a� 5-month��history�of�a�right�palpebral�swelling.�Physical�examination�revealed�a�right�palpebral�mass�that�was�approximately�3�cm�in�size�and�causing�mechani-cal� ptosis.� Right� cervical� lymphadenopathy� was� observed.� No� spleno-megaly�was�present.�The�white�blood�cell� count�was�120,000/mm3�com-prising� 43.1%� granulocytes,� 44%� lymphocytes,� 6.3%� monocytes,� and�6.6%�eosinophils.�The�hematocrit�was�36.4%,�and�the�platelet�count�was�287,000/mm3.�Magnetic�resonance�imaging�of�the�head�showed�a�supero-lateral�orbital�tissue�mass�that�invaded�the�right�lacrimal�gland�and�meas-ured�approximately�3�cm�in�width,�1�cm�in�height,�and�3.5�cm�in�antero-posterior�diameter.�Biopsy�of�the�orbital�mass�was�performed.�Histologi-cal� examination� demonstrated� fibroadipose� connective� tissue� including�diffuse�cellular�infiltrates.�The�cells�in�the�infiltrate�were�medium�to�large�in�size,�with�a�round�nucleus�containing�a�fine�chromatin�and�with�hyper-basophilic�scanty�cytoplasm�(fig.�1).�Mitotic� figures�were�abundant.� Im-munohistochemically,� the� tumor�cells�were�positive� for�CD19�(fig.�2�a),�CD20� (fig.� 2� b)� and� CD79a� (fig.� 2� c),� and� negative� for� TdT� (fig.� 2� d).�Based�on�these�findings,�the�tumor�was�diagnosed�as�DLBCL.�Computed�tomography�scans�showed�multiple�cervical,�mediastinal,�and�intra-perito-neal�lymph�node�involvement.�A�bone�marrow�(BM)�specimen�revealed�medullary� extension� of� the� lymphoma� (15%� lymphoma� cells).� A� cyto-genetic�BM�study�was�not�performed,�and�no� lymphoma�cells�were�de-tected�in�the�cerebrospinal�fluid.�The�patient�was�staged�as�having�stage�IV�lymphoma�according�to�the�Ann�Arbor�classification.�She�was�treated�according� to� the� group� B� of� the� LMB� 89� protocol� [3]� with� complete��remission� after� COPADM1� (cyclophosphamide,� oncovin,� prednisone,�adriamycin,�high-dose�methotrexate).�The�chemotherapy�was�completed�in�November�2009�with�a�persistent�complete�remission.�

In�August�2010,�during�a�routine�control,� the�patient�presented�with�an�elevated�white�blood�cell�count�(250,000/mm3�with�25%�neutrophils,�6%� lymphocytes,� 3%� eosinophils,� 2%� basophils,� 3%� erythroblasts,��40%�myelocytes�+�metamyelocytes,�18%�promyelocytes,�and�3%�blasts).�Hemoglobin� was� 10� g/dl,� and� the� platelet� count� was� 122,000/mm3.� On�physical�examination,�she�showed�splenomegaly�and�hepatomegaly�3�and�2�cm,�respectively�below�the�costal�margin.�BM�examination�showed�82%�granulopoiesis,� 10%� erythropoiesis� and� 4%� blasts,� and� no� morphology�consistent� with� myelodysplastic� syndrome� (MDS).� The� cytogenetic� BM�study� revealed� a� 46,XX,� t(4;9)(q13;p13),t(9;22)(q34;q11)-14� karyotype.�Reverse� transcription�polymerase� chain� reaction�analysis�performed�on�the�BM�aspirate�revealed�the�presence�of�an�e1a2�BCR/ABL�fusion�tran-script.�Based�on�these�findings,�the�diagnosis�of�accelerated�phase�CML�was�confirmed.�Treatment�with�hydroxyurea�and�allopurinol�was�started�with�normalization�of�leukocytosis�after�3�weeks.�Treatment�with�imatinib�

Fig. 1.�Hematoxylin�and�eosin�staining��of�orbital�mass��specimen�showing�dense�lymphoid��infiltrate�(original�magnification�×400).

Fig. 2.�Lymphoid�cells�staining��strongly�positive��with�a�CD19,�b�CD20,�and�c�CD79a,�and�d�negative�with�TdT�(original�magnification�×400).

a b

c d

Fig. 3.�Bone�marrow�showing�myeloid�blast�cells�(May-Grunwald-Giemsa�staining,�original�magnification�×100).

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Page 3: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature

692 Onkologie�2012;35:690–693 Zahra/Ben�Fredj/Ben�Youssef/Zaghouani/Chebchoub/Zaier/Badreddine/Braham/�Sennana/Khelif

(12�mg/m2�daily�for�5�days)�and�cytosine�arabinoside�(200�mg/m2�continu-ous�infusion�for�7�days)�in�conjunction�with�nilotinib�at�a�dose�of�300�mg�twice�a�day.�Hematological�remission�was�not�obtained,�and�the�patient�died�of�cerebral�hemorrhage.

Discussion

Treatment-related�MDS�(Tr-MDS)�and�AML�(Tr-AML)�are�well-known� complications� after� chemotherapy� for� various��hematologic�and�non-hematologic�malignancies�[5].�Philadel-phia� chromosome� (Ph)� has� been� reported� in� MDS� and� in��de�novo�AML�without�preceding�CML�[6].�In�our�case,�a�BM�examination�carried�out�in�August�2010�showed�no�evidence�of�MDS�or�AML,�confirming�the�diagnosis�of�CML.�Ph-posi-tive�CML�has�only�rarely�been�referred�to�as�a�therapy-related�disorder� in� patients� who� received� chemotherapy� for� prior��neoplasms� [7].� On� the� contrary,� more� frequent� are� reports��relating� to� lymphoproliferative� disorders� occurring� in� con-comitance� with� or� following� CML� [8].� Table� 1� shows� previ-ously�reported�cases�of�CML�secondary�to�NHL.�The�median�patient� age� was� 70� years� (range� 59–82� years),� the� median��latency�period�between�the�2�diseases�was�60�months,�and�the�majority�of�cases�were�diagnosed�in�chronic�phase�CML.�In�all�patients,� prior� chemotherapy� and/or� radiotherapy� and� the��latency� period� between� the� 2� diseases� strongly� suggested� a�treatment-related�CML�(Tr-CML)�[5,�9–13].

The�authors�suggested�that�the�time�interval�for�expansion�of� the�malignant�clone�was�at� least�16�months� [14].�Our�pa-tient� developed� CML� relatively� shortly� after� treatment� of�DLBCL�with�latency�time�of�only�9�months�between�the�2�dis-eases,� suggesting� the� hypothesis� of� non-treatment� related�CML� (nTr-CML)� occurring� as� well� as� a� primary� de� novo�

�disorder.�Indeed,�nTr-CML�as�a�second�malignancy�is�a�rare�entity� [15,� 16].� 9� case� reports� of� nTr-CML� occurring� in� pa-tients� with� previous� neoplasms,� who� had� not� been� treated�with� �chemotherapy,� are� summarized� in� table� 2.� The� latency�period�was�calculated�as�the�months�between�the�initial�diag-nosis�of�the�first�malignancy�and�the�appearance�of�CML.�All�patients�were�older�than�50�years�[5,�16–19].�Thus,�this�entity�was� not� previously� described� in� the� younger� population.� To�our� knowledge,� this� is� the� first� report� of� a� child� who� devel-oped�CML�as�a�second�malignancy�after�DLBCL.

nTr-CML�as�a�second�neoplasm�could�be�due�to�the�effects�of�immunological�alterations�produced�by�the�first�neoplasia.�In� fact,� the� role� of� impairment� of� the� immune� system� was��confirmed�by�the�development�of�CML�following�renal�trans-plantation�in�patients�receiving�azathioprine�with�or�without�prednisone� [20]� as� well� as� by� the� high� incidence� of� second��malignancies�due� to� immunological�deficiencies� in�hairy�cell�leukemia�[21]�and�chronic�lymphocytic�leukemia�[22].�In�our�case,� CML� development� could� be� related� to� immunological�alterations� associated� with� DLBCL.� Indeed,� in� a� recent� re-port,�the�authors�demonstrated�that�NHL�in�pediatric�patients�was�associated�with�elevated� levels�of� inflammatory�and� im-mune-regulating� cytokines� [23].�Furthermore,� the�possibility�of�CML�development� from�clonal�abnormalities�present�be-fore� treatment� for� lymphoma�cannot�be� ruled�out,� although�the�association�of�both�diseases�is�uncommon�in�the�younger�population.� Indeed,� some� cases� of� apparent� therapy-related�leukemia� and� myelodysplasia� have� been� found� under� closer�scrutiny� to� have� arisen� from� clonal� abnormalities� that� were�present� before� the� putative� treatment� insult� [24].� Unfortu-nately,� in�our�case,�no�cytogenetic�BM�study�was�performed�during�staging�for�DLBCL.

Table 1.�Reported�cases�of�chronic�myeloid�leukemia�(CML)�developing�after�non-Hodgkin’s�lymphoma�(NHL)

Case Author�[ref.] Sex Age,�years NHL�treatment Latency,�months CML�phase

1 Auerbach�et�al.�[9] M 66 CTX+VCR+ADR+RT 57 chronic2 Whang-Peng�et�al.�[5] F 77 COP ���NR84 chronic3 Cazzola�et�al.�[10] F 59 COP+RT 84 chronic4 Mele�et�al.�[11] M 64 CTX+VCR+RT 84 lymphoid�blast�crisis5 Bolanos-Meade�et�al.�[12] M 82 CHL+PDN 96 chronic6 Breccia�et�al.�[13] F 73 various�CHT�regimens�+�RT 228 chronic

M�=�Male;�F�=�female;�CTX�=�cyclophosphamide;�VCR�=�vincristine;�ADR�=�adriamycin;�RT�=�radiotherapy;��COP�=�CTX+VCR+PDN;�PDN�=�prednisone;�CHL�=�chlorambucil;�CHT�=�chemotherapy;�NR�=�not�reported.

Table 2.�Main�characteristics�of�the�non-treatment-related�chronic�myeloid�leukemia�patients�group

Author�[ref.] Sex Age,�years Initial�diagnosis Therapy Latency�period,�months

Whang-Peng�et�al.�[17] M 74 CLL none 36Whang-Peng�et�al.�[5] M 74 CLL none 24Reeves�et�al�[18] M 83 HCL none 17Hashimi�et�al.�[19] F 82 CLL none 53Giorgina�et�al.�[16]

Case�1 M 51 lung�cancer surgery 84Case�2 F 63 rectal�cancer surgery 61Case�3 M 72 prostate�cancer surgery 29Case�4 M 68 rectal�cancer surgery 118Case�5 M 77 bladder�cancer surgery 83

M�=�Male;�F�=�female;�CLL�=�chronic�lymphocytic�leukemia,�HCL�=�hairy�cell�leukemia.

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Page 4: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature

Onkologie�2012;35:690–693Secondary�Chronic�Myeloid�Leukemia 693

Imatinib�mesylate�has�shown�efficacy�and�safety�as�a�potent�inhibitor�of�the�constitutively�activated�ABL�tyrosine�kinase�which�is�crucial�to�the�pathogenesis�of�CML�[13].�According�to�the�literature,�secondary�Ph-positive�CML�responds�favor-ably�to�imatinib�mesylate�therapy�[25–27].�The�significant�re-sponse�to�imatinib�therapy�suggests�that�the�molecular�patho-genesis�of�secondary�CML�is�similar�to�that�of�primary�CML,�and�that�the�BCR-ABL�transcript�plays�a�similar�role�in�both�diseases.� In� accordance� with� this,� the� reported� cases� of� sec-ondary�CML�appear�to�have�the�same�course�and�prognosis�as�de�novo�CML�[7].�Contrary� to�what�has�been� reported,�our�patient� had� a� poor� response� to� imatinib� therapy� and� pro-gressed�to�the�blastic�phase.�Secondary�CML,�like�other�sec-ondary�malignancies,�may�occur�as�a�result�of�a�genetic�predis-position�to�cancer�or,�alternatively,�may�develop�as�a�result�of�genetic�damage�caused�by�chemo-radiotherapy�given�as�treat-ment� for� a� primary� tumor.� As� such,� secondary� CML� may��harbor�additional�genetic�aberrations�in�addition�to�the�BCR-

� 9� Auerbach� HE,� Stelmach� T,� LaGuette� JG,� et� al.:�Secondary�Ph�positive�CML�with�a�minority�mono-somy� 7� clone.� Cancer� Genet� Cytogenet� 1987;28:�173–178.

10� Cazzola� M,� Bergamashi� G,� Melazzini� M,� et� al.:�Chronic� myelogenous� leukemia� following� radio-therapy� and� chemotherapy� for�non-Hodgkin� lym-phoma.�Haematologica�1990;75:477–479.

11� Mele� L,� Pagano� L,� Equitani� F,� et� al.:� Lymphoid�blastic� crisis� in�Philadelphia� chromosome� positive�chronic�granulocytic�leukemia�following�high-grade�non-Hodgkin’s� lymphoma.� A� case� report� and� re-view�of�literature.�Haematologica�2000;85:544–547.

12� Bolanos-Meade�J,�Sarkodee-Adoo�C,�Khanwani�SL:�CML� after� treatment� for� lymphoid� malignancy:�therapy-related�CML�or�coincidence?�Am�J�Hema-tol�2002;71:139.

13� Breccia� M,� Martelli� M,� Cannella� L,� et� al.:��Rituximab� associated� to� imatinib� for� coexisting�therapy-related� chronic� myeloid� leukemia� and��relapsed�non-Hodgkin�lymphoma.�Leuk�Res�2008;�32:353–355.

14� Barman�E,�Strife�A,�Wisniewski�D,�et�al.:�Duration�of� the� preclinical� phase� of� chronic� myelogenous�leukaemia:�a�case�report.�Blood�1991;78:2969–2972.

15� Alsop�S,�Sanger�WG,�Elenitoba-Johnson�KS,�et�al.:�Chronic� myeloid� leukemia� as� a� secondary� malig-nancy�after�ALK-positive�anaplastic�large�cell�lym-phoma.�Hum�Pathol�2007;38:1576–1580.

16� Specchia�G,�Buquicchio�C,�Albano�F,�et�al.:�Non-treatment-related� chronic� myeloid� leukemia� as� a�second�malignancy.�Leuk�Res�2004;28:115–119.

17� Whang-Peng� J,�Gralnick� HR,� Johnson� RE,� et� al.:�Chronic�granulocytic�leukemia�during�the�course�of�chronic� lymphocytic� leukemia:� correlation� of�blood,� marrow,� and� spleen� morphology� and� cyto-genetics.�Blood�1974;43:333.

18� Reeves� JE,� Robbins� BA,� Pankey� LR,� et� al.:� The��simultaneous� occurrence� of� variant� hairy� cell��leukemia�and�chronic�phase�chronic�myelogenous�leukemia.�A�case�report.�Cancer�1995;75:2085.

19� Hashimi� L,� Al-Katib� A,� Mertelsmann� R,� et� al.:��Cytofluorometric� detection� of� chronic� myelocytic�leukemia� supervening� in� a� patient� with� chronic�lymphocytic�leukemia.�Am�J�Med�1986;�80:269.

20� Sanz� L,� Cervantes� F,� Esteve� J,� et� al.:� Chronic��myeloid�leukemia�after�renal�transplantation:�a�re-port�of�a�case�and�review�of�the�literature.�Sangre�1996;41:391.

21� Au�WY,�Klasa�RJ,�Gallagher�R,�et�al.:�Second�ma-lignancies� in� patients� with� hairy� cell� leukemia� in�British� Columbia:� a� 20-year� experience.� Blood�1998;92:1160.

22� Teichmann�JV,�Sieber�G,�Ludwig�D,�et�al.:�Chronic�myelocytic� leukemia� as� a� second� neoplasia� in� the�course� of� chronic� lymphocytic� leukemia.� Case� re-port� and� review�of� the� literature.�Leuk�Res�1986;�10:361.

23� Mellgren�K,�Hedegaard�CJ,�Schmiegelow�K,�et�al.:�Plasma� cytokine� profiles� at� diagnosis� in� pediatric�patients� with� non-Hodgkin� lymphoma.� J� Pediatr�Hematol�Oncol�2012;34:271–275.

24� Abruzzese�E,�Radford�JE,�Miller�JS,�et�al.:�Detec-tion�of�abnormal�pretransplant�clones�in�progenitor�cells� of� patients� who� developed� myelodysplasia�after� autologous� transplantation.� Blood� 1999;94:�1814–1819.

25� Ramanarayanan�J,�Dunford�LM,�Baer�MR,�et�al.:�Chronic�myeloid�leukemia�after�treatment�of�lym-phoid�malignancies:�response�to�imatinib�mesylate�and� favorable� outcomes� in� three� patients.� Leuk�Res�2006;30:701–705.

26� Waldman� D,� Weintraub� M,� Freeman� A,� et� al.:��Favorable� early� response� of� secondary� chronic��myeloid�leukemia�to�imatinib.�Am�J�Hematol�2004;�75:217–219.

27� Waller� CF,� Fetscher� S,� Lange� W:� Treatment-�related� chronic� myelogenous� leukemia.� Ann��Hematol�1999;78:341–354.

References

� 1� Miles� RR,� Raphael� M,� Carthy� K,� et� al.:� Pediatric�diffuse�large�B�cell�lymphoma�demonstrates�a�high�proliferation� index,� frequent-myc� protein� expres-sion,� and� a� high� incidence� of� germinal� center��subtype:� report� of� the� French-American-British�(FAB)� international� study� group.� Pediatr� Blood�Cancer�2008;51:369–374.

� 2� Ries�LAG,�Melbert�D,�Krapcho�M,�et�al.:�Cancer�incidence�and�survival�among�children�and�adoles-cents:� United� States� SEER� Program� 1975–1995.�National�Cancer�Institute,�Bethesda,�MD,�2008.

� 3� Patte�C,�Auperin�A,�Michon�J,�et�al.:�The�Société�Française� dʼOncologie� Pédiatrique� LMB89� proto-col:� highly� effective� multiagent� chemotherapy��tailored�to�the�tumor�burden�and�initial�response�in�561�unselected�children�with�B-cell�lymphomas�and�L3�leukemia.�Blood�2001;97:3370–3379.

� 4� Perel�Y,�Auvrignon�A,�Leblanc�T,�et�al.:�Treatment�of�childhood�acute�myeloblastic�leukemia:�dose�in-tensification� improves� outcome� and� maintenance�therapy�is�of�no�benefit�–�multicenter�studies�of�the�French� LAME� (Leucémie� Aiguë� Myéloblastique�Enfant)� Cooperative� Group.� Leukemia� 2005;19:�2082–2089.

� 5� Whang-Peng�J,�Young�RC,�Lee�EC,�et�al.:�Cytoge-netic� studies� in�patients�with�secondary� leukemia/dysmyelopietic�syndrome�after�different�treatment�modalities.�Blood�1988;71:403–414.

� 6� Keung�YK,�Beaty�M,�Bayard�L,�et�al.:�Philadelphia�chromosome� positive� myelodysplastic� syndrome�and�acute�myeloid� leukemia�–� retrospective�study�and� review� of� literature.� Leuk� Res� 2004;28:579–586.

� 7� Aguiar� RC:� Therapy-related� chronic� myeloid��leukemia:� an� epidemiological,� clinical� and� patho-genetic�appraisal.�Leuk�Lymphoma�1998;29:17–26.

� 8� Rodler� E,� Welborn� J,� Hatcher� S,� et� al.:� Blastic�mantle�cell�lymphoma�developing�concurrently�in�a�patient�with�chronic�myelogenous�leukaemia�and�a�review� of� the� literature.� Am� J� Hematol� 2004;75:�231–238.

ABL�translocation�and�may�thus�be�refractory�to�therapy�that�targets� only� the� BCR-ABL� protein� [26].� In� our� case,� the��patient� had� an� additional� t(4;9)� genetic� aberration,� and� this�may�explain�the�poor�response�to�imatinib�mesylate�therapy.�However,�further�studies�are�required�to�validate�this.

In�conclusion,�CML�following�DLBCL�has�not�been�previ-ously�described�in�the�younger�population.�To�our�knowledge,�this�is�the�first�report�of�a�child�developing�the�2�malignancies.�With�the�increased�use�of�cytogenetic�BM�studies�in�the�stag-ing�of� lymphoid�malignancies,� future�studies�may�be�able� to�clarify� the� question� of� whether� the� CML� clone� in� some� of�these�patients�existed�before�treatment�for�lymphoma.

Disclosure Statement

We�report�no�financial�support�and�no�potential�conflicts�of�interest.

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