Letter to the editor
A ca of acute myeloid leukemia initially treated as chronic lymphocytic
leukemia:what do we know about t(4;12)(q12;p13)?
Acute myeloid leukemia (AML)is the most common acute leukemia in adults,with incidence approaching 13,000cas in the United States in 2008.It is diagnod bad on the percentage of blasts in the peripheral blood or bone marrow smear,in addition to specific cytogenetic find-ings.The standard therapy in the United States is anthracy-cline with cytarabine in a 7þ3protocol.Among the rare chromosomal translocations reported in AML is t(4;12)(q12;p13),which has been documented in veral reports (e,for example,references [1,2])and has poor prognosis.This entity is characterized by atypical myeloblasts,which may be reported as lymphocytes and therefore can be described also as pudo-lymphocytes .Here we describe a ca of t(4;12)(q12;p13)AML that was resistant to conven-tional chemotherapy.Imatinib was also tried as a possible therapy targeted to the protein transcript CHIC2e ETV6,but was not effective.
A 64-year-old man of European origin prented to a local hospital with progressive generalized weakness in July 2008.He also reported a weight loss of ~9kg (20pounds)over 3months,with intermittent night sweats.No petechiae,rash,hepatosplenomegaly,or obvious lymphadenopathy were
obrved upon physical examination.At prentation,his white blood cell count was elevated (307Â109/L);his hemo-globin was 7.2g/dL,and platelets were 170Â109/L.The differential was read as 60%lymphocytes and ~30%prolym-phocytes.A peripheral blood smear was reported to show lymphocytes,prominence of prolymphocytes,few blasts,and many smudge cells,compatible microscopically with chronic lymphocytic leukemia (CLL).Flow cytometry and cytogenetic analysis from the peripheral blood were recom-mended and ordered,but were never done.A computed tomography scan confirmed the abnce of any mass or enlarged nodes.A hematology consultation was ordered,and treatment for CLL was initiated.
The patient initially had leukapheresis performed,to reduce the tumor burden before initiation of chemotherapy,and his white blood cell count dropped to 10Â109/L.No bone marrow biopsy was performed.After discussion of therapeutic options,the patient received a standard fludara-bine,cyclophosphamide,and rituximab regimen (FCR)for a total of five cycles.During therapy,neutropenia resulted in veral delays in therapy.His white blood cell counts ranged from 2.3Â109/L to 12Â109/L between cycles of chemotherapy,with a rapid elevation of the count towardfoody
the end of each cycle.No increa in blast number was noted on the differential,but lymphocyte counts remained elevated (70%of total)during the majority of complete blood count readings,includin
g both lymphocytes and pro-lymphocytes.Basophil counts ranged from 1%to 20%of white blood cells toward the end of each cycle.After initial treatment with FCR failed to achieve an adequate respon,the patient was referred to a local cancer center for further treatment recommendations,including stem cell transplant options.
On initial consultation,the patient was found to have a good performance status,although his blood tests indi-cated trilineage myelosuppression.His white blood count was noted to be 164Â109/L with 92%blasts;his hemo-globin was 9.1g/dL,and his platelets were 94Â109/L.The patient was admitted for leukapheresis,and a white blood cell count of 7Â109/L was obtained.The peripheral blood smear (Fig.1)showed numerous white cells with a vaguely lymphoid appearance,moderate in size and with mildly clumped chromatin,a single nucleolus,and a moderate amount of agranular basophilic cytoplasm.A comparison with the patient’s original blood smear from July 2008indicated similar appearance.His first bone marrow biopsy was reviewed,and the blast count was noted to be O 90%,all previously and mistakenly identified as ‘‘atypical lymphocytes.’’Flow cytometry confirmed the myeloid lineage of the blasts.HLA typing identified a possible matched unrelated donor with an ABCDR match,and HLA DQ1AG mismatch.
tahoeThe patient received induction therapy using standard idarubicin and cytarabine on a 7þ3protocol.At
day 13,a bone marrow biopsy revealed persistent blasts with no hypoplasia,and the peripheral blood differential indicated 90%myeloid blasts.Cytogenetic analysis (Fig.2)revealed t(4;12)(q12;p13)in all 20metaphas analyzed and del(5q)(35)in 2of 10metaphas (not shown).After failure with two lines of therapy (i.e.,the idarubicin and cytarabine 7þ3and the fludarabine-bad FCR protocols),the patient was put on an imatinib and gemtuzumab chemotherapy regimen.The rationale for this third line of treatment included that (a)the blasts were O 80%positive for CD 33and (b)the patient’s translocation included the protein transcript of the ETV6gene.Patients with similar tran-scripts of the ETV6protein have been reported to be responsive to imatinib,such as t(5;12)in chronic
0165-4608/$-e front matter Ó2010Elvier Inc.All rights rerved.doi:
10.1016/j.cancergencyto.2010.09.004
myelomonocytic leukemia (CMML)(e,for example,references cited by Han et al.[3]).The prent patient was given one do of gemtuzumab at 9mg/m 2with continuous imatinib therapy at 400mg daily.A repeat bone marrow biopsy on day 9indicated persistent AML.Fourth-line therapy included gemtuzumab,intermediate-do cy-tarabine,and mitoxantrone (MIDAM protocol),with an increa in imatinib do to 800mg.A repeat bone marrow aspirate indicated no leukemic respon.The patient was placed on palliative care and nt home.
Acute myeloid leukemia is defined by the World Health Organization (WHO)as myeloblasts exceeding 20%or more of bone marrow white cells [4].The determination of the myeloid lineage is usually done through at least three-color flow cytometry or by traditional immunohisto-chemistry.Myeloid origin may also be suggested if the myeloperoxida (CD13,CD33)or monocytic markers (NSE,CD11c,CD14,and CD64)are positive.In the peripheral blood smear,myeloblasts are traditionally large cells with high nuclear-to-cytoplasm ratio and with nucleoli.Although the cells can contain a pink or red rodlike structure (Auer rods),Auer rods are not found all the time.Auer rods are the only indicator of myeloid origin by light microscopy.
The International Workshop on Chronic Lymphocytic Leukemia defined CLL as the prence of an absolute lymphocyte count exceeding 5,000/cm 2[5].The clonality of B-cells in CLL should also be confirmed by flow cytom-etry.In CLL,cells coexpress CD5and B-cell surface antigens (CD19,CD20,and CD23).A bone marrow exam-ination is not required for the diagnosis of CLL,although it is recommended before therapy was initiated.In the periph-eral blood smear the leukemic cells are commonly small,mature lymphocytes with den nuclei and aggregated chromatin but without discernible nucleoli;there is a narrow border of clear basophilic cytoplasm.Atypical
cells,
Fig.1.Peripheral blood smear.Arrows indicate myeloblasts (pudo-
lymphocytes).
在线学习韩语Fig.2.Karyogram.Arrows indicate translocated chromosomes.
349
Letter to the editor /Cancer Genetics and Cytogenetics 203(2010)348e 351
cleaved cells,or prolymphocytes should not make up more than55%of the blood lymphocytes;otherwi,B-cell pro-lymphocytic leukemia should be suspected.Cytogenetic analysis,whether traditional analysis orfluorescence in situ hybridization,is important for both AML and CLL, although much more important in for AML in diagnosis, prognosis,and therapy[6].The translocation t(4;12) (q12;p13)is one of the rarer translocations en in cas of AML.
The t(4;12)(q12;p13)aberration(Table1)has been re-ported in both myeloid and lymphoid malignancies,and it has been reported in children with B-cell acute lympho-blastic leukemia,but not in adults[1,2,7e9].The translo-cation of CHIC2to the ETV6gene leads to the fusion transcript CHIC2e ETV6.The ETV6gene(alias TEL), located on chromosome12p,is involved in veral malig-nancies,including pre-B cell ALL with t(12;21)(p13;q22), CMML with t(5;12)(q33;p13),and AML with t(9;12;14) [10].The CHIC2gene deletion on4q11in myeloid neoplasms is associated with the PDGFRA rearrangement or in systemic mastocytosis with eosinophilia[11].It also correlates with a clinical respon to imatinib.Imatinib is also effective in patients with CMML who have the t(5;12)(q33;p13)aberration involving the PDGFRB and ETV6genes[12].
Acute myeloid leukemia with a t(4;12)(q12;p13)aberra-tion is a specific entity,one that shares some characteristics with both acute myeloid leukemia and lymphocytic leukemia.Peripheral basophilia has been reported.Myeloid blasts are large cells and have significant amount of cyto-plasm and look like prolymphocytes(pudo-lymphocytes). Often dysplasia is en in all erythroid,granulocytic,and megakaryocytic lineages.Immunophenotypically,myeloid blasts share positivity for CD13,CD34,HLA-DR,c-kit, and an aberrant CD7,suggesting a stem cell origin.About half of reported cas are AML-M0.In a review of15cas with this translocation,complete remission was achieved in about one third of patients,and overall survival ranged from a few months to51months[1].In a review of an addi-tional ca,a CHIC2e ETV6fusion transcript was found but not ETV6e CHIC2[7].Perhaps becau of the rarity of the translocation,no evidence for utility of tyrosine kina inhibitors has been documented in AML with t(4;12)(q12;p13).Nonetheless,in support of therapeutic benefit,(a)both t(5;12)and t(4;12)involve the ETV6gene and produce fusion transcripts and(b)evidence in patients with CMML involving t(5;12)and similar fusion transcripts indicates responsiveness to imatinib[13].
Becau only scarce data exist suggesting activity of imatinib in this tting,we instituted standard induction at prentation.Once failure was documented,however, we cho to u imatinib in combination with gemtuzumab; unfortunately,this combination was not successful. Reasons for lack
of respon may include resistance specif-ically to imatinib,resistance to chemotherapy and gemtuzu-mab,and additional cytogenetic abnormalities,including deletion of5q,that place this leukemia among the more refractory variants of myelodysplasia.The5q deletion in the prent ca could also have affected the respon of the malignant clone to tyrosine kina inhibition,which rais the question of using alternative therapies,such as lenalidomide[14].Evidence for refractoriness to therapy has been reported in a cond patient who had both t(4;12) (q12;p13)and deletion of5q35and did not respond to therapy[7].
Acute myeloid leukemia with t(4;12)(q12;p13)is a rare entity that denotes an early hematopoietic genetic disrup-tion and manifests with circulating myeloblasts that look like prolymphocytes.Immunophenotyping suggests a stem cell origin.The prognosis for patients with this transloca-tion appears poor,and further rearch is warranted. Improved understanding of the pathophysiology of the translocation is necessary in order tofind more tailored, effective therapies and thus obtain improved survival in the highly resistant cas.
Aref Al-Kalilss>中国四六级考试网
Department of Leukemia
M.D.Anderson Cancer Center
Houston,TX77030
E-mail address:aal2@mdanderson
Mohamad Cherry
Hematology and Medical Oncology Section
Department of Internal Medicine
Oklahoma University
Oklahoma City,OK73126
Kristopher Kimmell
College of Medicine
Oklahoma University
Oklahoma City,OK73126
apartheid
Jennifer Holter
Bone Marrow Transplant Section
Department of Internal Medicine
华尔街英语 软件
Oklahoma University
Oklahoma City,OK73126
Table1
Characteristics of t(4;12)(q12;p13)acute myeloid leukemia
Lineage,adult myeloid(AML;M0e50%)
吸血鬼日记第一季19Lineage,pediatric lymphoid(B-ALL)
Immunophenotype CD13þ,CD34þ,HLA-DRþ,
c-kitþ,CD7þ
Transcript protein CHIC2e ETV6
Peripheral smear basophilia,pudo-lymphocytes
Bone marrow dysplasia in all three lineages
Prognosis Poor
Complete remission,%33
Median overall survival,mo8
350Letter to the editor/Cancer Genetics and Cytogenetics203(2010)348e351
William Kern
Bradley Gehrs
Department of Pathology
otherfaith
Oklahoma University
Oklahoma City,OK73126
Howard Ozer
Hematology and Medical Oncology Section
Department of Internal Medicine
Oklahoma University
Oklahoma City,OK73126
George Selby
Bone Marrow Transplant Section
花纸Department of Internal Medicine
Oklahoma University
Oklahoma City,OK73126
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