chronic myeloid leukemia as a secondary malignancy after lymphoma in a child. a case report and...
TRANSCRIPT
![Page 1: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature](https://reader031.vdocuments.net/reader031/viewer/2022020614/575094b91a28abbf6bbb880a/html5/thumbnails/1.jpg)
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.
Dow
nloa
ded
by:
Lule
a T
ekni
ska
Uni
vers
itet
13
0.24
0.43
.43
- 8/
25/2
013
12:1
5:52
PM
![Page 2: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature](https://reader031.vdocuments.net/reader031/viewer/2022020614/575094b91a28abbf6bbb880a/html5/thumbnails/2.jpg)
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).
Dow
nloa
ded
by:
Lule
a T
ekni
ska
Uni
vers
itet
13
0.24
0.43
.43
- 8/
25/2
013
12:1
5:52
PM
![Page 3: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature](https://reader031.vdocuments.net/reader031/viewer/2022020614/575094b91a28abbf6bbb880a/html5/thumbnails/3.jpg)
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.
Dow
nloa
ded
by:
Lule
a T
ekni
ska
Uni
vers
itet
13
0.24
0.43
.43
- 8/
25/2
013
12:1
5:52
PM
![Page 4: Chronic Myeloid Leukemia as a Secondary Malignancy after Lymphoma in a Child. A Case Report and Review of the Literature](https://reader031.vdocuments.net/reader031/viewer/2022020614/575094b91a28abbf6bbb880a/html5/thumbnails/4.jpg)
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.
Dow
nloa
ded
by:
Lule
a T
ekni
ska
Uni
vers
itet
13
0.24
0.43
.43
- 8/
25/2
013
12:1
5:52
PM